Abstract
Alzheimer disease (AD) is a multifactorial disorder involving oxidative stress, neuroinflammation, impairments in energy metabolism, and excitotoxicity. AD affects several brain regions such as entorhinal cortex, hippocampus, basal forebrain and amygdale, which exhibit synaptic loss resulting in extensive brain atrophy. In vulnerable brain regions, AD is characterized by the accumulation of extracellular neuritic plaques and intracellular neurofibrillary tangles. The neurofibrillary tangles consist largely of hyperphosphorylated twisted filaments of the microtubule-associated protein Tau. Extracellular neuritic plaques are deposits of Aβ that are derived via sequential proteolytic cleavages of the APP. Clinically, AD patients present with symptoms of memory loss, altered personality and behavior, and impaired executive function. Neurochemically, AD is accompanied by profound biochemical alterations in multiple pathways including increased turnover of membrane phospholipid, sphingolipid, and cholesterol metabolism and increase in phospholipid-, sphingolipid-, and cholesterol-derived lipid mediators. The severity of AD pathology is associates with number of reactive astrocytes and activated microglia in the brain. Both neurons and glial cells contribute to the induction, maintenance, and progression of neuroinflammation and oxidative stress in AD by releasing proinflammatory cytokines and generating reactive oxygen and nitrogen species, which contribute to neurodegeneration in AD. Accumulating evidence suggests that AD also involves increases in metal ions (iron, copper, and zinc), nitric oxide generation, reduction in expression of trophic factors, dysfunction of the ubiquitin–proteasome system, depletion of endogenous antioxidants, and expression of proapoptotic proteins leading to synaptic and neuronal loss.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575
Adlard PA, Parncutt JM, Finkelstein DI, Bush AI (2010) Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer’s disease? J Neurosci 30:1631–1636
Agostinho P, Cunha RA, Oliveira C (2010) Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des 16:2766–2778
Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE (2008) Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 65:1509–1517
Albensi BC, Mattson MP (2000) Evidence for the involvement of TNF and NF-κB in hippocampal synaptic plasticity. Synapse 35:151–159
Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K (1997) Abnormal phosphorylation of Tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal Tau. Proc Natl Acad Sci U S A 94:298–303
Altamura S, Muckenthaler MU (2009) Iron toxicity in diseases of aging: Alzheimer’s disease, Parkinson’s disease and atherosclerosis. J Alzheimers Dis 16:879–895
Alzheimer’s Association (2010) Alzheimer’s disease facts and figures. Alzheimers Dement 6:158–194
Alzheimer’s Association (2012) 2011 Alzheimer’s diseases facts and figures: prevalence. Alzheimers Dement 7:12–13
Alzheimer’s Association (2013) Alzheimer’s disease facts and figures. Alzheimer Dementia 9:208–245
Amaducci L, Tesco G (1994) Aging as a major risk for degenerative diseases of the central nervous system. Curr Opin Neurol 7:283–286
An K, Jung JH, Jeong AY, Kim HG, Jung SY, Lee K, Kim HJ, Kim SJ, Jeong TY, Son Y, Kim HS, Kim JH (2014) Neuritin can normalize neural deficits of Alzheimer’s disease. Cell Death Dis 5, e1523
Andrasi E, Pali N, Molnar Z, Kosel S (2005) Brain aluminum, magnesium and phosphorus contents of control and Alzheimer-diseased patients. J Alzheimers Dis 7:273–284
Andreyev AY, Fahy E, Guan Z, Kelly S, Li X, McDonald JG, Milne S, Myers D, Park H, Ryan A, Thompson BM, Wang E, Zhao Y, Brown HA, Merrill AH, Raetz CR, Russell DW, Subramaniam S, Dennis EA (2010) Subcellular organelle lipidomics in TLR-4-activated macrophages. J Lipid Res 51:2785–2797
Arboleda G, Morales LC, Benítez B, Arboleda H (2009) Regulation of ceramide-induced neuronal death: cell metabolism meets neurodegeneration. Brain Res Rev 59:333–346
Ariga T, McDonald MP, Yu RK (2008) Thematic review series: sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer’s disease—a review. J Lipid Res 49:1157–1175
Arioka M, Tsukamoto M, Ishiguro K, Kato R, Sato K, Imahori K, Uchida T (1993) Tau protein kinase II is involved in the regulation of the normal phosphorylation state of Tau protein. J Neurochem 60:461–468
Arnaud L, Robakis NK, Figueiredo-Pereira ME (2006) It may take inflammation, phosphorylation and ubiquitination to ‘tangle’ in Alzheimer’s disease. Neurodegener Dis 3:313–319
Arnaud LT, Myeku N, Figueiredo-Pereira ME (2009) Proteasome-caspase-cathepsin sequence leading to Tau pathology induced by prostaglandin J2 in neuronal cells. J Neurochem 110:328–342
Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776
Augustinack JC, Schneider A, Mandelkow EM, Hyman BT (2002) Specific Tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103:26–35
Avila J, Gomez de Barreda E, Engel T, Lucas JJ, Hernandez F (2010) Tau phosphorylation in hippocampus results in toxic gain-of-function. Biochem Soc Trans 38:977–980
Ayton S, Lei P, Bush AI (2013) Metallostasis in Alzheimer’s disease. Free Radic Biol Med 62:76–89
Bai Y, Li Q, Yang J, Zhou X, Yin X, Zhao D (2008) p75(NTR) activation of NF-kappaB is involved in PrP106–126-induced apoptosis in mouse neuroblastoma cells. Neurosci Res 62:9–14
Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL (2000) Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 275:36803–36810
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377:1019–1031
Bansal MP, Shalini S (2005) Effect of cholesterol and 7-beta hydroxycholesterol on glutathione status and nitric oxide production in murine peritoneal macrophages. Indian J Exp Biol 43:503–508
Barbagallo M, Belvedere M, Di Bella G, Dominguez LJ (2011) Altered ionized magnesium levels in mild-to-moderate Alzheimer’s disease. Magnes Res 24:S115–S121
Barbusinski K (2009) Fenton reaction—controversy concerning the chemistry. Ecol Chem Eng 16:347–358
Barnes K, Matsas R, Hooper NM, Turner AJ, Kenny AJ (1988a) Endopeptidase-24.11 is striosomally ordered in pig brain, and in contrast to aminopeptidase N and peptidyl dipeptidase A (“angiotensin converting enzyme”), is a marker for a set of striatal efferent fibres. Neuroscience 27(3):799–817
Barnes K, Turner AJ, Kenny AJ (1988b) Electronmicroscopic immunocytochemistry of pig brain shows that endopeptidase-24.11 is localized in neuronal membranes. Neurosci Lett 94:64–69
Barnes K, Doherty S, Turner AJ (1995) Endopeptidase-24.11 is the integral membrane peptidase initiating degradation of somatostatin in the hippocampus. J Neurochem 64:1826–1832
Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS, Beyreuther K, Masters CL, Parker MW, Cappai R (2003) Structure of the Alzheimer’s disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J Biol Chem 278:17401–17407
Barrier L, Ingrand S, Fauconneau B, Page G (2008) Gender-dependent accumulation of ceramides in the cerebral cortex of the APP(SL)/PS1Ki mouse model of Alzheimer’s disease. Neurobiol Aging 31:1843–1853
Beraldo FH, Arantes CP, Santos TG, Queiroz NG, Young K, Rylett RJ, Markus RP, Prado MA, Martins VR (2010) Role of alpha7 nicotinic acetylcholine receptor in calcium signaling induced by prion protein interaction with stress-inducible protein 1. J Biol Chem 285:36542–36550
Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009) An operational definition of epigenetics. Genes Dev 23:781–783
Bertram L (2009) Alzheimer’s disease genetics current status and future perspectives. Int Rev Neurobiol 84:167–184
Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31:454–463
Bhat NR (2010) Linking cardiometabolic disorders to sporadic Alzheimer’s disease: a perspective on potential mechanisms and mediators. J Neurochem 115:551–562
Biasini E, Turnbaugh JA, Unterberger U, Harris DA (2012) Prion protein at the crossroads of physiology and disease. Trends Neurosci 35:92–103
Bjørbaek C, Buchholz RM, Davis SM, Bates SH, Pierroz DD, Gu H, Neel BG, Myers MG Jr, Flier JS (2001) Divergent roles of SHP-2 in ERK activation by leptin receptors. J Biol Chem 276:4747–4755
Björkhem I, Lütjohann D, Diczfalusy U, Ståhle L, Ahlborg G, Wahren J (1998) Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res 39:1594–1600
Björkhem I, Andersson U, Ellis E, Alvelius G, Ellegard L, Diczfalusy U, Sjövall J, Einarsson C (2001) From brain to bile. Evidence that conjugation and omega-hydroxylation are important for elimination of 24S-hydroxycholesterol (cerebrosterol) in humans. J Biol Chem 276:37004–37010
Blennow K, Hampel H (2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2:605–613
Bloom GS (2014) Amyloid-β and Tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71:505–508
Blurton-Jones M, Laferla FM (2006) Pathways by which Abeta facilitates Tau pathology. Curr Alzheimer Res 3:437–448
Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, Russell DW, Björkhem I (2001) On the turnover of brain cholesterol in patients with Alzheimer’s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett 314:45–48
Bohr VA (2002) Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells. Free Radic Biol Med 32:804–812
Boland K, Behrens M, Choi D, Manias K, Perlmutter DH (1996) The serpin-enzyme complex receptor recognizes soluble, non toxic amyloid-β peptide but not aggregated, cytotoxic amyloid-β peptide. J Biol Chem 271:18032–18044
Bolognin S, Messori L, Zatta P (2009) Metal ion physiopathology in neurodegenerative disorders. Neuromolecular Med 11:223–238
Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG (2012) An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Abeta oligomers. J Clin Invest 122:1339–1353
Borger E, Aitken L, Du H, Zhang W, Gunn-Moore FJ, Yan SS (2013) Is amyloid binding alcohol dehydrogenase a drug target for treating Alzheimer’s disease? Curr Alzheimer Res 10:21–29
Bosco D, Fava A, Plastino M, Montaecini T, Puja A (2011) Possible implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis. J Cell Mol Med 15:1807–1821
Bourassa MW, Leskovjan AC, Tappero RV, Farquhar ER, Colton CA, Van Nostrand WE, Miller LM (2013) Elevated copper in the amyloid plaques and iron in the cortex are observed in mouse models of Alzheimer’s disease that exhibit neurodegeneration. Biomed Spectrosc Imaging 2:129–139
Boyle PA, Wilson RS, Yu L, Barr AM, Honer WG, Schneider JA, Bennett DA (2013) Much of late life cognitive decline is not due to common neurodegenerative pathologies. Ann Neurol 74:478–489
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259
Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99–12510
Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP (2005) The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care 28:726–735
Brasnjevic I, Hof PR, Steinbusch HW, Schmitz C (2008) Accumulation of nuclear DNA damage or neuron loss: molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases. DNA Repair (Amst) 7:1087–1097
Brazil DP, Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26:657–664
Brewer GJ (1998) Age-related toxicity to lactate, glutamate, and beta-amyloid in cultured adult neurons. Neurobiol Aging 19:561–568
Brewer GJ (2010) Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories. Exp Gerontol 45:173–179
Breydo L, Uversky VN (2011) Role of metal ions in aggregation of intrinsically disordered proteins in neurodegenerative diseases. Metallomics 3:1163–1180
Brookmeyer R, Gray S, Kawas C (1998) Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health 88:1337–1342
Brooksbank BW, McGovern J (1989) Gangliosides in the brain in adult Down’s syndrome and Alzheimer’s disease. Mol Chem Neuropathol 11:143–156
Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10:333–344
Burns A, Iliffe S (2009) Alzheimer’s disease. Br Med J 338:b158
Cannon JR, Greenamyre JT (2011) The role of environmental exposures in neurodegeneration and neurodegenerative diseases. Toxicol Sci 124:225–250
Caraci F, Battaglia G, Busceti C, Biagioni F, Mastroiacovo F, Bosco P, Drago F, Nicoletti F, Sortino MA, Copani A (2008) TGF-beta 1 protects against Abeta-neurotoxicity via the phosphatidylinositol-3-kinase pathway. Neurobiol Dis 30:234–242
Carulla P, Bribián A, Rangel A, Gavín R, Ferrer I, Caelles C, Del Río JA, Llorens F (2011) Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding. Mol Biol Cell 22:3041–3054
Cencioni C, Spallotta F, Martelli F, Valente S, Mai A, Zeiher AM, Gaetano C (2013) Oxidative stress and epigenetic regulation in ageing and age-related diseases. Int J Mol Sci 14:17643–17663
Chabrier MA, Cheng D, Castello NA, Green KN, LaFerla FM (2014) Synergistic effects of amyloid-beta and wild-type human Tau on dendritic spine loss in a floxed double transgenic model of Alzheimer’s disease. Neurobiol Dis 64:107–117
Chakravarthy B, Menard M, Ito S, Gaudet C, Dal Pra I, Armato U, Whitfield J (2012) Hippocampal membrane-associated p75NTR levels are increased in Alzheimer’s disease. J Alzheimers Dis 30:675–684
Chamberlain R, Wengenack TM, Poduslo JF, Garwood M, Jack CR Jr (2011) Magnetic resonance imaging of amyloid plaques in transgenic mouse models of Alzheimer’s disease. Curr Med Imaging Rev 7:3–7
Chauhan NB, Siegel GJ, Feinstein DL (2005) Propentofylline attenuates Tau hyperphosphorylation in Alzheimer’s Swedish mutant model Tg2576. Neuropharmacology 48:93–104
Chen F, Yu G, Arawaka S, Nishimura M, Kawarai T, Yu H, Tandon A, Supala A, Song YQ, Rogaeva E, Milman P, Sato C, Yu C, Janus C, Lee J, Song L, Zhang L, Fraser PE, St George-Hyslop PH (2001) Nicastrin binds to membrane-tethered Notch. Nat Cell Biol 3:751–754
Chen L, Lee HM, Greeley GH Jr, Englander EW (2007) Accumulation of oxidatively generated DNA damage in the brain: a mechanism of neurotoxicity. Free Radic Biol Med 42:385–393
Chen S, Yadav SP, Surewicz WK (2010) Interaction between human prion protein and amyloid-beta (Abeta) oligomers: role of N-terminal residues. J Biol Chem 285:26377–26383
Chiarini A, Dal Pra I, Whitfield JF, Armato U (2006) The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines. Ital J Anat Embryol 111:221–246
Chin J, Palop JJ, Puoliväli J, Massaro C, Bien-Ly N, Gerstein H, Scearce-Levie K, Masliah E, Mucke L (2005) Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease. J Neurosci 25:9694–9703
Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS, Li L (2004) Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases. J Biol Chem 279:13256–13264
Chouliaras L, Rutten BP, Kenis G, Peerbooms O, Visser PJ, Verhey F, van Os J, Steinbusch HW, van den Hove DL (2010) Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog Neurobiol 90:498–510
Chouliaras L, Mastroeni D, Delvaux E, Grover A, Kenis G, Hof PR, Steinbusch HW, Coleman PD, Rutten BP, van den Hove DL (2013) Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging 34:2091–2099
Chuang JC, Jones PA (2007) Epigenetics and microRNAs. Pediatr Res 61:24R–29R
Ciani L, Salinas PC (2005) WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci 6:351–362
Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, Pontecorvo MJ, Hefti F, Carpenter AP, Flitter ML, Krautkramer MJ, Kung HF, Coleman RE, Doraiswamy PM, Fleisher AS, Sabbagh MN, Sadowsky CH, Reiman EP, Zehntner SP, Skovronsky DM; AV45-A07 Study Group (2011) Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 305:275–283
Clarke JR, Lyra E, Silva NM, Figueiredo CP, Frozza RL, Ledo JH, Beckman D, Katashima CK, Razolli D, Carvalho BM, Frazão R, Silveira MA, Ribeiro FC, Bomfim TR, Neves FS, Klein WL, Medeiros R, LaFerla FM, Carvalheira JB, Saad MJ, Munoz DP, Velloso LA, Ferreira ST, De Felice FG (2015) Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation. EMBO Mol Med 7:190–210
Cole SL, Vassar R (2007) The Alzheimer’s disease β-secretase enzyme, BACE1. Mol Neurodegener 2:22
Conejo R, Lorenzo M (2001) Insulin signaling leading to proliferation, survival, and membrane ruffling in C2C12 myoblasts. J Cell Physiol 187:96–108
Connor JR, Snyder BS, Beard JL, Fine RE, Mufson EJ (1992a) Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer’s disease. J Neurosci Res 31:327–335
Connor JR, Menzies SL, St Martin SM, Mufson EJ (1992b) A histochemical study of iron, transferrin, and ferritin in Alzheimer’s diseased brains. J Neurosci Res 31:75–83
Coppedè F, Migliore L (2009) DNA damage and repair in Alzheimer’s disease. Curr Alzheimer Res 6:36–47
Cordy JM, Hooper NM, Turner AJ (2003) Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 100:11735–11740
Costa RM, Drew J, Silva AJ (2005) Notch to remember. Trends Neurosci 28:429–435
Costantini C, Weindruch R, Della Valle G, Puglielli L (2005) A TrkA-to-p75NTR molecular switch activates amyloid β-peptide generation during aging. Biochem J 391:59–67
Costantini C, Scrable H, Puglielli L (2006) An aging pathway controls the TrkA to p75NTR receptor switch and amyloid β peptide generation. EMBO J 25:1997–2006
Cotman CW (2005) The role of neurotrophins in brain aging: a perspective in honor of Regino Perez-Polo. Neurochem Res 30:877–881
Crichton RR, Dexter DT, Ward RJ (2011) Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm 118:301–314
Cui W, Sun Y, Wang Z, Xu C, Xu L, Wang F, Chen Z, Peng Y, Li R (2011) Activation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levels. Neurochem Res 36:1910–1921
Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, Barnham KJ (2001) Alzheimer’s disease amyloid-β binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem 276:20466–20473
Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci U S A 17:2070–2075
Dandona P (2002) Endothelium, inflammation, and diabetes. Curr Diab Rep 2:311–315
Dasari B, Prasanthi JR, Marwarha G, Singh BB, Ghribi O (2010) The oxysterol 27-hydroxycholesterol increases b-amyloid and oxidative stress in retinal pigment epithelial cells. BMC 10:22
Davison AN (1965) Brain sterol metabolism. Adv Lipid Res 3:171–196
Dawkins E, Small DH (2014) Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer’s disease. J Neurochem 129:756–769
Day JJ, Sweatt JD (2011) Epigenetic mechanisms in cognition. Neuron 70:813–829
de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, Spires-Jones TL, Hyman BT (2010) Caspase activation precedes and leads to tangles. Nature 464:1201–1204
De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL (2007) A beta oligomers induce neuronal oxidative stress through an N-methyl-d-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282:11590–11601
De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, Bigio EH, Jerecic J, Acton PJ, Shughrue PJ, Chen-Dodson E, Kinney GG, Klein WL (2009a) Alzheimer’s disease-type neuronal Tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging 29:1334–1347
De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL (2009b) Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A 106:1971–1976
de la Monte SM (2013) Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art. Expert Opin Drug Deliv 10:1699–1709
de la Monte SM (2009) Insulin resistance and Alzheimer’s disease. BMB Rep 42:475–481
de la Monte SM, Tong M (2013) Insulin resistance and metabolic failure underlie Alzheimer disease. In: Farooqui T, Farooqui AA (eds) Metabolic syndrome and neurological disorders. Wiley, Oxford, UK, pp 1–30
de la Monte SM, Tong M (2014) Brain metabolic dysfunction at the core of Alzheimer’s disease. Biochem Pharmacol 88:548–559
de la Monte SM, Wands JR Jr (2008) Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2:1101–1113
Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25:1010–1022
Deibel MA, Ehmann WD, Markesbery WR (1996) Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress. J Neurol Sci 143:137–142
Delcroix JD, Valletta JS, Wu C, Hunt SJ, Kowal AS, Mobley WC (2003) NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals. Neuron 39:69–84
Demuro A, Smith M, Parker I (2011) Single-channel Ca2+ imaging implicates Aβ1-42 amyloid pores in Alzheimer’s disease pathology. J Cell Biol 195:515–524
Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584
Desbène C, Malaplate-Armand C, Youssef I, Garcia P, Stenger C, Sauvée M, Fischer N, Rimet D, Koziel V, Escanyé MC, Oster T, Kriem B, Yen FT, Pillot T, Olivier JL (2012) Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit. Neurobiol Aging 33:1123.e17–e29
Dickson JR, Kruse C, Montagna DR, Finsen B, Wolfe MS (2013) Alternative polyadenylation and miR-34 family members regulate Tau expression. J Neurochem 127:739–749
Doherty GH (2011) Obesity and the ageing brain: could leptin play a role in neurodegeneration? Curr Gerontal Geriatr Res 2011:708154
Doherty GH, Beccano-Kelly D, Yan SD, Gunn-Moore FJ, Harvey J (2012) Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β. Neurobiol Aging 34:226–237
Du JL, Poo MM (2004) Rapid BDNF-induced retrograde synaptic modification in a developing retinotectal system. Nature 429:878–883
Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105
Duce JA, Bush AI (2010) Biological metals and Alzheimer’s disease: implications for therapeutics and diagnostics. Prog Neurobiol 92:1–18
Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI (2010) Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell 142:857–867
Egana JT, Zambrano C, Nunez MT, Gonzalez-Billault C, Maccioni RB (2003) Iron-induced oxidative stress modify Tau phosphorylation patterns in hippocampal cell cultures. Biometals 16:215–223
El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD (1996) Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils. Nature 382:716–719
Emmerzaal TL, Kiliaan AJ, Gustafson DR (2015) 2003-2013: a decade of body mass index, Alzheimer’s disease, and dementia. J Alzheimers Dis 43:739–755
Englander EW (2008) Brain capacity for repair of oxidatively damaged DNA and preservation of neuronal function. Mech Ageing Dev 129:475–482
Escribano L, Simón AM, Gimeno E, Cuadrado-Tejedor M, López de Maturana R, García-Osta A, Ricobaraza A, Pérez-Mediavilla A, Del Río J, Frechilla D (2010) Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and Tau pathology. Neuropsychopharmacology 35:1593–1604
Evans MC, Barnes J, Nielsen C, Kim LG, Clegg SL, Blair M, Leung KK, Douiri A, Boyes RG, Ourselin S, Fox NC (2010) Volume changes in Alzheimer’s disease and mild cognitive impairment: cognitive associations. Eur Radiol 20:674–682
Extance A (2010) Alzheimer’s failure raises questions about disease-modifying strategies. Nat Rev Drug Discov 9:749–751
Fahrenholz F (2007) Alpha-secretase as a therapeutic target. Curr Alzheimer Res 4:412–417
Famer D, Meaney S, Mousavi M, Nordberg A, Bjorkhem I, Crisby M (2007) Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the a-secretase pathway. Biochem Biophys Res Commun 20:46–50
Fang CL, Wu WH, Liu Q, Sun X, Ma Y, Zhao YF, Li YM (2010) Dual functions of beta-amyloid oligomer and fibril in Cu(II)-induced H2O2 production. Regul Pept 163:1–6
Farooqui AA (2009a) Beneficial effects of fish oil on human brain. Springer, New York
Farooqui AA (2009b) Hot topics in neural membrane lipidology. Springer, New York, NY
Farooqui AA (2010a) Neurochemical aspects of neurotraumatic and neurodegeneratine diseases. Springer, New York
Farooqui AA (2010b) Studies on plasmalogen-selective phospholipase A2 in brain. Mol Neurobiol 41:267–273
Farooqui AA (2011) Lipid mediators and their metabolism in the brain. Springer, New York
Farooqui AA (2013) Metabolic syndrome: an important risk factor for Stroke, Alzheimer, and depression. Springer, New York
Farooqui AA (2014) Inflammation and oxidative stress in neurological disorders. Springer, New York
Farooqui AA (2015) High calorie diet and human brain: metabolic consequences of long term consumption. Springer, New York
Farooqui AA, Horrocks LA (2007) Glycerophospholipids in the brain: phospholipases A2 in neurological disorders. Springer, New York, NY
Farooqui AA, Rapoport SI, Horrocks LA (1997) Membrane phospholipid alterations in Alzheimer’s disease: deficiency of ethanolamine plasmalogens. Neurochem Res 22:523–527
Farooqui AA, Horrocks LA, Farooqui T (2000) Deacylation-reacylation of neural membrane glycerophospholipids, a matter of life and death. J Mol Neurosci 14:123–133
Farooqui AA, Ong WY, Horrocks LA (2003) Plasmalogens, docosahexaenoic acid and neurological disorders. Adv Exp Med Biol 544:335–354
Farooqui AA, Horrocks LA, Farooqui T (2007) Modulation of inflammation in brain: a matter of fat. J Neurochem 101:577–599
Farooqui AA, Ong WY, Horrocks LA (2008) Neurochemical aspects of excitotoxicity. Springer, New York
Farooqui AA, Ong WY, Farooqui T (2010) Lipid mediators in the nucleus: their potential contribution to Alzheimer’s disease. Biochim Biophys Acta 1801:906–916
Farooqui AA, Farooqui T, Panza F, Frisardi V (2012) Metabolic syndrome as a risk factor for neurological disorders. Cell Mol Life Sci 69:741–762
Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan G (2010) Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13:423–430
Ferrer I (2009) Altered mitochondria, energy metabolism, voltage-dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimer’s disease. J Bioenerg Biomembr 41:425–431
Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N (2004) Obesity-related leptin regulates Alzheimer’s Abeta. FASEB J 18:1870–1878
Figueiredo-Pereira ME, Rockwell P, Schmidt-Glenewinkel T, Serrano P (2015) Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration. Front Mol Neurosci 7:104
Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH (2007) Recovery of learning and memory is associated with chromatin remodelling. Nature 447:178–182
Flier JS (2004) Obesity wars: molecular progress confronts an expanding epidemic. Cell 116:337–350
Folwell J, Cowan CM, Ubhi KK, Shiabh H, Newman TA, Shepherd D, Mudher A (2010) Aβ exacerbates the neuronal dysfunction caused by human Tau expression in a Drosophila model of Alzheimer’s disease. Exp Neurol 223:401–409
Fonteh AN, Chiang J, Cipolla M, Hale J, Diallo F, Chirino A, Arakaki X, Harrington MG (2013) Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer’s disease. J Lipid Res 54:2884–2897
Fox NC, Schott JM (2004) Imaging cerebral atrophy: normal ageing to Alzheimer’s disease. Lancet 363:392–394
Frazzini V, Rockabrand E, Mocchegiani E, Sensi SL (2006) Oxidative stress and brain aging: is zinc the link? Biogerontology 7:307–314
Frederickson CJ, Suh SW, Silva D, Frederickson CJ, Thompson RB (2000) Importance of zinc in the central nervous system: the zinc-containing neuron. J Nutr 130:1471S–1483S
Frisoni GB, Rozzini L, Gozzetti A, Binetti G, Zanetti O, Bianchetti A, Trabucchi M, Cummings JL (1999) Behavioral syndromes in Alzheimer’s disease: description and correlates. Dement Geriatr Cogn Disord 10:130–138
Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, Lund EG (2001) 27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276:38378–38387
Fujino T, Lee WC, Nedivi E (2003) Regulation of cpg15 by signaling pathways that mediate synaptic plasticity. Mol Cell Neurosci 24:538–554
Fujino T, Wu Z, Lin WC, Phillips MA, Nedivi E (2008) cpg15 and cpg15-2 constitute a family of activity-regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival. J Comp Neurol 507:1831–1845
Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet al, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL (2003) Caspase cleavage of Tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A 100:10032–10037
Garza JC, Guo M, Zhang W, Lu XY (2008) Leptin increases adult hippocampal neurogenesis in vivo and in vitro. J Biol Chem 283:18238–18247
Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, Xu H (2001) Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci 21:2561–2570
Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM (2003) Initiation and synergistic fibrillization of Tau and α-synuclein. Science 300:636–640
Gleichmann M, Mattson MP (2011) Neuronal calcium homeostasis and dysregulation. Antioxid Redox Signal 14:1261–1273
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706
Golde TE, Dickson D, Hutton M (2006) Filling the Gaps in the abeta; cascade hypothesis of Alzheimer’s disease. Curr Alzheimer Res 3:421–430
Gong CX, Iqbal K (2008) Hyperphosphorylation of microtubule-associated protein Tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem 15:2321–2328
Gong Y, Chang L, Viola K, Lacor P, Lambert M, Finch C, Krafft GA, Klein WL (2003) Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A 100:10417–10422
Gräff J, Kim D, Dobbin MM, Tsai L-H (2011) Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol Rev 91:603–649
Grant WB, Campbell A, Itzhaki RF, Savory J (2002) The significance of environmental factors in the etiology of Alzheimer’s disease. J Alzheimers Dis 4:179–189
Greco SJ, Sarkar S, Johnston JM, Zhu X, Su B, Casadesus G, Ashford JW, Smith MA, Tezapsidis N (2008) Leptin reduces Alzheimer’s disease-related Tau phosphorylation in neuronal cells. Biochem Biophys Res Commun 376:536–541
Greco SJ, Sarkar S, Johnston JM, Tezapsidis N (2009) Leptin regulates Tau phosphorylation and amyloid through AMPK in neuronal cells. Biochem Biophys Res Commun 380:98–104
Grimm MO, Grimm HS, Patzold AJ, Zinser EG, Halonen R, Duering M, Tschäpe JA, De Strooper B, Müller U, Shen J (2005) Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin. Nat Cell Biol 27:1118–1123
Grimm MO, Grimm HS, Hartmann T (2007) Amyloid beta as a regulator of lipid homeostasis. Trends Mol Med 13:337–344
Grimm MO, Rothhaar TL, Grösgen S, Burg VK, Hundsdörfer B, Haupenthal VJ, Friess P, Kins S, Grimm HS, Hartmann T (2011a) Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP). J Nutr Biochem 23:1214–1223
Grimm MO, Kuchenbecker J, Grösgen S, Burg VK, Hundsdörfer B, Rothhaar TL, Friess P, de Wilde MC, Broersen LM, Penke B, Péter M, Vígh L, Grimm HS, Hartmann T (2011b) Docosahexaenoic acid reduces amyloid beta production via multiple pleiotropic mechanisms. J Biol Chem 286:14028–14039
Grimm MO, Zinser EG, Grösgen S, Hundsdörfer B, Rothhaar TL, Burg VK, Kaestner L, Bayer TA, Lipp P, Müller U, Grimm HS, Hartmann T (2012) Amyloid precursor protein (APP) mediated regulation of ganglioside homeostasis linking Alzheimer’s disease pathology with ganglioside metabolism. PLoS One 7, e34095
Grimm MO, Zimmer VC, Lehmann J, Grimm HS, Hartmann T (2013) The impact of cholesterol, DHA, and sphingolipids on Alzheimer’s disease. Biomed Res Int 2013:814390
Gu X, Sun J, Li S, Wu X, Li L (2013) Oxidative stress induces DNA demethylation and histone acetylation in SH-SY5Y cells: potential epigenetic mechanisms in gene transcription in Aβ production. Neurobiol Aging 34:1069–1079
Guan Z, Wang Y, Cairns NJ, Lantos PL, Dallner G, Sindelar PJ (1999) Decrease and structural modifications of phosphatidylethanolamine plasmalogen in the brain with Alzheimer disease. J Neuropathol Exp Neurol 58:740–747
Guo Z, Jiang H, Xu X, Duan W, Mattson MP (2008) Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. J Biol Chem 283:1754–1763
Haan MN (2006) Therapy insight: type 2 diabetes mellitus and the risk of late-onset alzheimer’s disease. Nat Clin Pract Neurol 2:159–166
Haass C, Mandelkow E (2010) Fynτ-amyloid: a toxic triad. Cell 142:356–358
Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112
Hambidge M (2000) Human zinc deficiency. J Nutr 130:1344S–1349S
Han X (2007) Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer’s disease: a tale of shotgun lipidomics. J Neurochem 103(Suppl 1):171–179
Han X (2010) The pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer’s disease. Mol Neurobiol 41:97–106
Han X, Holtzman DM, McKeel DW Jr (2001) Plasmalogen deficiency in early Alzheimer’s disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry. J Neurochem 77:1168–1180
Han X, Holtzman DM, McKeel DW Jr, Kelley J, Morris JC (2002) Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J Neurochem 82:809–818
Hanger DP, Anderton BH, Noble W (2009) Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med 15:112–119
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356
Hartmann D, Tournoy J, Saftig P, Annaert W, De Strooper B (2001) Implication of APP secretases in notch signaling. J Mol Neurosci 17:171–181
Harvey J, Shanley LJ, O’Malley D, Irving AJ (2005) Leptin: a potential cognitive enhancer? Biochem Soc Trans 33:1029–1032
He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R, Shen Y (2007) Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 178:829–841
He X, Huang Y, Li B, Gong CX, Schuchman EH (2010) Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol Aging 31:398–408
Heerssen HM, Pazyra MF, Segal RA (2004) Dynein motors transport activated Trks to promote survival of target-dependent neurons. Nat Neurosci 7:596–604
Heneka MT, O’Banion MK (2007) Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184:69–91
Henneman WJ, Sluimer JD, Barnes J, van der Flier WM, Sluimer IC, Fox NC, Scheltens P, Vrenken H, Barkhof F (2009) Hippocampal atrophy rates in Alzheimer disease: added value over whole brain volume measures. Neurology 72:999–1007
Herholz K (2012) Use of FDG PET as an imaging biomarker in clinical trials of Alzheimer’s disease. Biomark Med 6:431–439
Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023
Hirano T, Murakami M, Fukada T, Nishida K, Yamasaki S, Suzuki T (2008) Roles of zinc and zinc signaling in immunity: zinc as an intracellular signaling molecule. Adv Immunol 97:149–176
Ho A, Sudhof TC (2004) Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid-beta precursor protein cleavage. Proc Natl Acad Sci U S A 101:2548–2553
Holden KF, Lindquist K, Tylavsky FA, Rosano C, Harris TB, Yaffe K (2009) Serum leptin level and cognition in the elderly: findings from the Health ABC Study. Neurobiol Aging 30:1483–1489
Holland WL, Summers SA (2008) Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev 29:381–402
Hong S, Ostaszewski BL, Yang T, O’Malley TT, Jin M, Yanagisawa K, Li S, Bartels T, Selkoe DJ (2014) Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82:308–319
Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104:1433–1439
Hsieh RH, Hou JH, Hsu HS, Wei YH (1994) Age-dependent respiratory function decline and DNA deletions in human muscle mitochondria. Biochem Mol Biol Int 32:1009–1022
Hu N, Yu JT, Tan L, Wang YL, Sun L, Tan L (2013) Nutrition and the risk of Alzheimer’s disease. Biomed Res Int 2013:524820
Hu NW, Nicoll AJ, Zhang D, Mably AJ, O’Malley T, Purro SA, Terry C, Collinge J, Walsh DM, Rowan MJ (2014) mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo. Nat Commun 5:3374
Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, Tanzi RE, Bush AI (1999) The Aβ peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38:7609–7616
Huang Y, Tanimukai H, Liu F, Iqbal K, Grunake-Iqbal I, Gong CX (2004) Elevation of the level and activity of acid ceramidase in Alzheimer’s disease brain. Eur J Neurosci 20:3489–3497
Hughes TM, Lopez OL, Evans RW, Kamboh MI, Williamson JD, Klunk WE, Mathis CA, Price JC, Cohen AD, Snitz BE, Dekosky ST, Kuller LH (2014) Markers of cholesterol transport are associated with amyloid deposition in the brain. Neurobiol Aging 35:802–807
Hung YH, Bush AI, La Fontaine S (2013) Links between copper and cholesterol in Alzheimer’s disease. Front Physiol 4:111
Illenberger S, Zheng-Fischhofer Q, Preuss U, Stamer K, Baumann K, Trinczek B, Biernat J, Godemann R, Mandelkow EM, Mandelkow E (1998) The endogenous and cell cycle-dependent phosphorylation of Tau protein in living cells: implications for Alzheimer’s disease. Mol Biol Cell 9:1495–1512
Illi B, Colussi C, Grasselli A, Farsetti A, Capogrossi MC, Gaetano C (2009) NO sparks off chromatin: tales of a multifaceted epigenetic regulator. Pharmacol Ther 123:344–352
Inestrosa NC, Arenas E (2010) Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 11:77–86
Iqbal K, Liu F, Gong CX, Alonso AC, Grundke-Iqbal I (2009) Mechanisms of Tau-induced neurodegeneration. Acta Neuropathol 118:53–69
Iwata A, Nagata K, Hatsuta H, Takuma H, Bundo M, Iwamoto K, Tamaoka A, Murayama S, Saido T, Tsuji S (2014) Altered CpG methylation in sporadic Alzheimer’s disease is associated with APP and MAPT dysregulation. Hum Mol Genet 23:648–656
Jahn H (2013) Memory loss in Alzheimer’s disease. Dialogues Clin Neurosci 15:445–454
Jana A, Pahan K (2004) Fibrillar amyloid-beta peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer’s disease. J Biol Chem 279:51451–51459
Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53:474–481
Jeong J, Eide DJ (2013) The SLC39 family of zinc transporters. Mol Aspects Med 34:612–619
Jetten AM (2009) Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 7:45–59
Jiang D, Li X, Williams R, Patel S, Men L, Wang Y, Zhou F (2009) Ternary complexes of iron, amyloid-β, and nitrilotriacetic acid: binding affinities, redox properties, and relevance to iron-induced oxidative stress in Alzheimer’s disease. Biochemistry 48:7939–7947
Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA (2000) Statins and the risk of dementia. Lancet 356:1627–1631
Johnston AM, Pirola L, Van Obberghen E (2003) Molecular mechanisms of insulin receptor substrate protein-mediated modulation of insulin signalling. FEBS Lett 546:32–36
Kaether C, Haass C (2004) A lipid boundary separates APP and secretases and limits amyloid beta-peptide generation. J Cell Biol 167:809–812
Kalanj S, Kracun I, Rosner H, Cosovic C (1991) Regional distribution of brain gangliosides in Alzheimer’s disease. Neurol Croat 40:269–281
Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F, Prince M, Stewart R, Wimo A, Zhang ZX, Antuono P; World Federation of Neurology Dementia Research Group (2008) Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol 7:812–826
Kandalepas PC, Vassar R (2012) Identification and biology of β-secretase. J Neurochem 120(Suppl 1):S55–S61
Kang J, Muller-Hill B (1990) Differential splicing of Alzheimer’s disease amyloid A4 precursor RNA in rat tissues: PreA4(695) mRNA is predominantly produced in rat and human brain. Biochem Biophys Res Commun 166:1192–1200
Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736
Kang HS, Angers M, Beak JY, Wu X, Gimble JM, Wada T, Xie W, Collins JB, Grissom SF, Jetten AM (2007) Gene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism. Physiol Genomics 31:281–294
Kanoski SE, Davidson TL (2011) Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol Behav 103:59–68
Katsel P, Li C, Haroutunian V (2007) Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer’s disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer’s disease? Neurochem Res 32:845–856
Katura T, Moriya T, Nakahata N (2010) 15-Deoxy-delta 12,14-prostaglandin J2 biphasically regulates the proliferation of mouse hippocampal neural progenitor cells by modulating the redox state. Mol Pharmacol 77:601–611
Katzman R, Saitoh T (1991) Advances in Alzheimer’s disease. FASEB J 5:278–286
Kawahara M (2010) Neurotoxicity of beta-amyloid protein: oligomerization, channel formation and calcium dyshomeostasis. Curr Pharm Des 16:2779–2789
Kessels HW, Nguyen LN, Nabavi S, Malinow R (2010) The prion protein as a receptor for amyloid-beta. Nature 466:E3–E4
Khosravani H, Zhang Y, Tsutsui S, Hameed S, Altier C, Hamid J, Altier C, Hamid J, Chen L, Villemaire M, Ali Z, Jirik FR, Zamponi GW (2008) Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. J Cell Biol 181:551–565
Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303
Kim J, Lee HJ, Lee KW (2010) Naturally occurring phytochemicals for the prevention of Alzheimer’s disease. J Neurochem 112:1415–1430
Kim J, Yoon H, Basak J, Kim J (2014) Apolipoprotein E in synaptic plasticity and Alzheimer’s disease: potential cellular and molecular mechanisms. Mol Cells 37:767–776
Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ (2003) γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2. Proc Natl Acad Sci U S A 100:6382–6387
Kitazawa M, Cheng D, Laferla FM (2009) Chronic copper exposure exacerbates both amyloid and Tau pathology and selectively dysregulates cdk5 in a mouse model of AD. J Neurochem 108:1550–1560
Kleene R, Loers G, Langer J, Frobert Y, Buck F, Schachner M (2007) Prion protein regulates glutamate-dependent lactate transport of astrocytes. J Neurosci 27:12331–12340
Klewpatinond M, Davies P, Bowen S, Brown DR, Viles JH (2008) Deconvoluting the Cu2+ binding modes of full-length prion protein. J Biol Chem 283:1870–1881
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Ann Neurol 55:306–319
Knowles JK, Rajadas J, Nguyen TV, Yang T, LeMieux MC, Vander Griend L, Ishikawa C, Massa SM, Wyss-Coray T, Longo FM (2009) The p75 neurotrophin receptor promotes amyloid-β(1–42)-induced neuritic dystrophy in vitro and in vivo. J Neurosci 29:10627–10637
Kojro E, Postina R (2009) Regulated proteolysis of RAGE and AbetaPP as possible link between type 2 diabetes mellitus and Alzheimer’s disease. J Alzheimers Dis 16:865–878
Kong Y, Wu J, Yuan L (2014) MicroRNA expression analysis of adult-onset Drosophila Alzheimer’s disease model. Curr Alzheimer Res 11:882–891
Konietzko U (2012) AICD nuclear signaling and its possible contribution to Alzheimer’s disease. Curr Alzheimer Res 9:200–216
König HG, Kögel D, Rami A, Prehn JH (2005) TGF-{beta}1 activates two distinct type I receptors in neurons implications for neuronal NF-{kappa}B signaling. J Cell Biol 168:1077–1086
Kopan R, Goate A (2000) A common enzyme connects notch signaling and Alzheimer’s disease. Genes Dev 14:2799–2806
Koponen E, Lakso M, Castrén E (2004) Overexpression of the full-length neurotrophin receptor trkB regulates the expression of plasticity-related genes in mouse brain. Brain Res Mol Brain Res 130:81–94
Kotti T, Head DD, McKenna CE, Russell DW (2008) Biphasic requirement for geranylgeraniol in hippocampal long-term potentiation. Proc Natl Acad Sci U S A 105:11394–11399
Krogh-Madsen R, Plomgaard P, Keller P, Keller C, Pedersen BK (2004) Insulin stimulates interleukin-6 and tumor necrosis factor-alpha gene expression in human subcutaneous adipose tissue. Am J Physiol Endocrinol Metab 286:E234–E238
Kumar S, Walter J (2011) Phosphorylation of amyloid beta (Aβ) peptides – a trigger for formation of toxic aggregates in Alzheimer’s disease. Aging (Albany, NY) 3:PMC3184981
Kuner PR, Schubenel RC, Hertel C (1998) β-amyloid binds to p75NTR and activates NF-κB in human neuroblastoma cells. J Neurosci Res 54:798–804
Labouèbe G, Liu S, Dias C, Zou H, Wong JC, Karunakaran S, Clee SM, Phillips AG, Boutrel B, Borgland SL (2013) Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nat Neurosci 16:300–308
Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24:10191–10200
Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27:796–807
Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25:11693–11709
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95:6448–6453
Landry GJ, Liu-Ambrose T (2014) Buying time: a rationale for examining the use of circadian rhythm and sleep interventions to delay progression of mild cognitive impairment to Alzheimer’s disease. Front Aging Neurosci 6:325
Lasagna-Reeves CA, Sengupta U, Castillo-Carranza D, Gerson JE, Guerrero-Munoz M, Troncoso JC, Jackson GR, Kayed R (2014) The formation of Tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes. Acta Neuropathol Commun 2:56
Lauren J, Gimbel D, Nygaard H, Gilbert J, Strittmatter S (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457:1128–1132
Leandro P, Gomes CM (2008) Protein misfolding in conformational disorders: rescue of folding defects and chemical chaperoning. Mini Rev Med Chem 8:901–911
Lee HG, Zhu X, Castellani RJ, Nunomura A, Perry G, Smith MA (2007) Amyloid-β in Alzheimer disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther 321(3):823–829
Lee H-K, Kumar P, Fu Q, Rosen KM, Querfurth HW (2009) The insulin/Akt signaling pathway is targeted by intracellular β-amyloid. Mol Biol Cell 20:1533–1544
Lee JC, Simonyi A, Sun AY, Sun GY (2010) Phospholipases A2 and neural membrane dynamics: implications for Alzheimer’s disease. J Neurochem 116:813–819
Leoni V (2009) Oxysterols as markers of neurological disease – a review. Scan J Clin Lab Invest 69:22–25
Leoni V, Solomon A, Kivipelto M (2010) Links between ApoE, brain cholesterol metabolism, Tau and amyloid beta-peptide in patients with cognitive impairment. Biochem Soc Trans 38:1021–1025
Lessmann V, Gottmann K, Malcangio M (2003) Neurotrophin secretion: current facts and future prospects. Prog Neurobiol 69:341–374
Li YM, Lai MT, Xu M, Huang Q, DiMuzio-Mower J, Sardana MK, Shi XP, Yin KC, Shafer JA, Gardell SJ (2000) Presenilin 1 is linked with gamma -secretase activity in the detergent solubilized state. Proc Natl Acad Sci U S A 97:6138–6143
Li T, Ma G, Cai H, Price DL, Wong PC (2003) Nicastrin is required for assembly of presenilin/γ-secretase complexes to mediate notch signaling and for processing and trafficking of β-amyloid precursor protein in mammals. J Neurosci 23:3272–3277
Li Z, Melandri F, Berdo I, Jansen M, Hunter L, Wright S, Valbrun D, Figueiredo-Pereira ME (2004a) Delta12-Prostaglandin J2 inhibits the ubiquitin hydrolase UCH-L1 and elicits ubiquitin-protein aggregation without proteasome inhibition. Biochem Biophys Res Commun 319:1171–1180
Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, Beach T, Sue L, Sabbagh M, Cai H, Wong P, Price D, Shen Y (2004b) Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci U S A 101:3632–3637
Li LM, Liu QH, Qiao JT, Zhang C (2009) Aβ31–35-induced neuronal apoptosis is mediated by JNK-dependent extrinsic apoptosis pathway. Neurosci Bull 25:361–366
Li W, Yu J, Huang X, Abumaria N, Zhu Y, Huang X, Xiong W, Pen C, Liu X-C, Chui D, Liu G (2014) Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer’s disease mouse model. Mol Brain 7:65
Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S (2009) Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA 302:2565–2572
Linkous DH, Flinn JM, Koh JY, Lanzirotti A, Bertsch PM, Jones BF, Giblin LJ, Frederickson CJ (2008) Evidence that the ZNT3 protein controls the total amount of elemental zinc in synaptic vesicles. J Histochem Cytochem 56:3–6
Liu W, Dou F, Feng J, Yan Z (2001) RACK1 is involved in β-amyloid impairment of muscarinic regulation of GABAergic transmission. Neurobiol Aging 32:1818–1826
Liu Y, Qin L, Wilson BC, An L, Hong J-S, Liu B (2002) Inhibition by naloxone stereoisomers of β-amyloid peptide (1-42)-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons. J Pharmacol Exp Ther 302:1212–1219
Liu D, Xu Y, Feng Y, Liu H, Shen X, Chen K, Ma J, Jiang H (2006) Inhibitor discovery targeting the intermediate structure of beta-amyloid peptide on the conformational transition pathway: implications in the aggregation mechanism of beta-amyloid peptide. Biochemistry 45:10963–10972
Liu H, Li W, Ahmad M, Miller TM, Rose ME, Poloyac SM, Uechi G, Balasubramani M, Hickey RW, Graham SH (2011) Modification of ubiquitin-C-terminal hydrolase-L1 by cyclopentenone prostaglandins exacerbates hypoxic injury. Neurobiol Dis 41:318–328
Longo FM, Massa SM (2008) Small molecule modulation of p75 neurotrophin receptor functions. CNS Neurol Disord Drug Targets 7:63–70
Lorenzo A, Yuan M, Zhang Z, Paganetti PA, Sturchler-Pierrat C, Staufenbiel M, Mautino J, Vigo FS, Sommer B, Yankner BA (2000) Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer’s disease. Nat Neurosci 3:460–464
Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF, Sathler LB, Brito-Moreira J, Amaral OB, Silva CA, Freitas-Correa L, Espírito-Santo S, Campello-Costa P, Houzel JC, Klein WL, Holscher C, Carvalheira JB, Silva AM, Velloso LA, Munoz DP, Ferreira ST, De Felice FG (2013) TNF-alpha mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer’s beta-amyloid oligomers in mice and monkeys. Cell Metab 18:831–843
Lovell MA, Markesbery WR (2008) Oxidatively modified RNA in mild cognitive impairment. Neurobiol Dis 29:169–175
Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci 158:47–52
Lukiw WJ, Andreeva TV, Grigorenko AP, Rogaev EI (2013) Studying micro RNA function and dysfunction in Alzheimer’s disease. Front Genet 3:327
Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW (2003) Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem 278:22980–22988
Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R (2001) Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nat Neurosci 4:231–232
Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304:448–452
Lutjohann D, Papassotiropoulos A, Bjorkhem I, Locatelli S, Bagli M, Oehring RD, Schlegel U, Jessen F, Rao ML, von Bergmann K, Heun R (2000) Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res 41:195–198
Ma H, Lesne S, Kotilinek L, Steidl-Nichols JV, Sherman M, Younkin L, Younkin S, Forster C, Sergeant N, Delacourte A, Vassar R, Citron M, Kofuji P, Boland LM, Ashe KH (2007) Involvement of beta-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. Proc Natl Acad Sci U S A 104:8167–8172
Mandelkow EM, Biernat J, Drewes G, Gustke N, Trinczek B, Mandelkow E (1995) Tau domains, phosphorylation, and interactions with microtubules. Neurobiol Aging 16:355–362, discussion 362–353
Mandelkow EM, Schweers O, Drewes G, Biernat J, Gustke N, Trinczek B, Mandelkow E (1996) Structure, microtubule interactions, and phosphorylation of Tau protein. Ann N Y Acad Sci 777:96–106
Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E (2003) Clogging of axons by Tau, inhibition of axonal traffic and starvation of synapses. Neurobiol Aging 24:1079–1085
Mantha AK, Sarkar B, Tell G (2013) A short review on the implications of base excision repair pathway for neurons: relevance to neurodegenerative diseases. Mitochondrion 16:38–49
Mao X, Ye J, Zhou S, Pi R, Dou J, Zang L, Chen X, Chao X, Li W, Liu M, Liu P (2012) The effects of chronic copper exposure on the amyloid protein metabolisim associated genes’ expression in chronic cerebral hypoperfused rats. Neurosci Lett 518:14–18
Martic S, Rains MK, Kraatz HB (2013) Probing copper/Tau protein interactions electrochemically. Anal Biochem 442:130–137
Martin L, Latypova X, Wilson CM et al (2013) Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev 12:289–309
Martins IJ, Berger T, Sharman MJ, Verdile G, Fuller SJ, Martins RN (2009) Cholesterol metabolism and transport in the pathogenesis of Alzheimer’s disease. J Neurochem 111:1275–1308
Marwarha G, Ghribi O (2012) Leptin signaling and Alzheimer’s disease. Am J Neurodegener Dis 1:245–265
Marwarha G, Dasari B, Prasanthi JR, Schommer J, Ghribi O (2010a) Leptin reduces the accumulation of Abeta and phosphorylated Tau induced by 27-hydroxycholesterol in rabbit organotypic slices. J Alzheimers Dis 19:1007–1019
Marwarha G, Dasari B, Prabhakara JP, Schommer J, Ghribi O (2010b) β-Amyloid regulates leptin expression and Tau phosphorylation through the mTORC1 signaling pathway. J Neurochem 115:373–384
Marwarha G, Raza S, Prasanthi JR, Ghribi O (2013) Gadd153 and NF-κB crosstalk regulates 27-hydroxycholesterol-induced increase in BACE1 and β-amyloid production in human neuroblastoma SH-SY5Y cells. PLoS One 8, e70773
Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW Jr, Morris JC (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56:127–129
Mast N, Norcross R, Andersson U, Shou M, Nakayama L, Bjorkhem I, Pikuleva IA (2003) Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry 42:14284–14292
Mateos L, Akterin S, Gil-Bea FJ, Spulber S, Rahman A, Björkhem I, Schultzberg M, Flores-Morales A, Cedazo-Minguez A (2009) Activity-regulated cytoskeleton-associated protein in rodent brain is down-regulated by high fat diet in vivo and by 27-hydroxycholesterol in vitro. Brain Pathol 19:69–80
Matsuzaki K, Kato K, Yanagisawa K (2010) Abeta polymerization through interaction with membrane gangliosides. Biochim Biophys Acta 1801:868–877
Mattson MP (2004) Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders. Ann N Y Acad Sci 1012:37–50
Matus A (1994) Stiff microtubules and neuronal morphology. Trends Neurosci 17:19–22
McCord MC, Aizenman E (2014) The role of intracellular zinc release in aging, oxidative stress, and Alzheimer’s disease. Front Aging Neurosci 6:77
McCoy MK, Tansey MG (2008) TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 5:45
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of department of health and human services task force on Alzheimer’s disease. Neurology 34:939–944
Mclauren Dorrance A, Graham D, Dominiczak A, Fraser R (2000) Inhibition of nitric oxide synthesis increases erythrocyte membrane fluidity and unsaturated fatty acid content. Am J Hypertens 13:1194–1202
McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS (2010) Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem 93:546–553
Meadowcroft MD, Connor JR, Smith MB, Yang QX (2009) MRI and histological analysis of beta-amyloid plaques in both human Alzheimer’s disease and APP/PS1 transgenic mice. J Magn Reson Imaging 29:997–1007
Metcalfe MJ, Huang Q, Figueiredo-Pereira ME (2012) Coordination between proteasome impairment and caspase activation leading to TAU pathology: neuroprotection by cAMP. Cell Death Dis 3, e326
Meziane H, Dodart JC, Mathis C, Little S, Clemens J, Paul SM, Ungerer A (1998) Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci U S A 95:12683–12688
Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, Crowell T, Cate RL, McCoy JM, Pepinsky RB (2004) LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci 7:221–228
Millan MJ (2013) An epigenetic framework for neurodevelopmental disorders: from pathogenesis to potential therapy. Neuropharmacology 68:2–82
Mitani Y, Akashiba H, Saita K, Yarimizu J, Uchino H, Okabe M, Asai M, Yamasaki S, Nozawa T, Ishikawa N, Shitaka Y, Ni K, Matsuoka N (2014) Pharmacological characterization of the novel γ-secretase modulator AS2715348, a potential therapy for Alzheimer’s disease, in rodents and nonhuman primates. Neuropharmacology 79:412–419
Mocchegiani E, Bertoni-Freddari C, Marcellini F, Malavolta M (2005) Brain, aging and neurodegeneration: role of zinc ion availability. Prog Neurobiol 75:367–390
Morante S (2008) The role of metals in beta-amyloid peptide aggregation: X-Ray spectroscopy and numerical simulations. Curr Alzheimer Res 5:508–524
Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Titani K, Ihara K (1995) Proline-directed and non-proline-directed phosphorylation of PHF-Tau. J Biol Chem 270:823–829
Morris M, Maeda S, Vossel K, Mucke L (2011) The many faces of Tau. Neuron 70:410–426
Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2:a006338
Münzberg H, Myers MG Jr (2005) Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 8:566–570
Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 63:71–124
Naeve GS, Ramakrishnan M, Kramer R, Hevroni D, Citri Y et al (1997) Neuritin: a gene induced by neural activity and neurotrophins that promotes neuritogenesis. Proc Natl Acad Sci U S A 94:2648–2653
Nalivaeva NN, Belyaev ND, Kerridge C, Turner AJ (2014) Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer’s disease. Front Aging Neurosci 6:235
Nathlie P, Jean-Noel O (2008) Processing of amyloid precursor protein and amyloid peptide neurotoxicity. Curr Alzheimer Res 5:92–99
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381
Niedowicz DM, Studzinski CM, Weidner AM, Platt TL, Kingry KN, Beckett TL, Bruce-Keller AJ, Keller JN, Murphy MP (2013) Leptin regulates amyloid β production via the γ-secretase complex. Biochim Biophys Acta 1832:439–444
Nielsen E, Severin F, Backer JM, Hyman AA, Zerial M (1999) Rab5 regulates motility of early endosomes on microtubules. Nat Cell Biol 1:376–382
Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981–989
Nistico R, Cavallucci V, Piccinin S, Macri S, Pignatelli M, Mehdawy B, Blandini F, Laviola G, Lauro D, Mercuri NB, D’Amelio M (2012) Insulin receptor beta-subunit haploinsufficiency impairs hippocampal late-phase LTP and recognition memory. Neuromolecular Med 14:262–269
Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW (2001) Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413:794–795
Nolte C, Gore A, Sekler I, Kresse W, Hershfinkel M, Hoffman A, Kettenmann H, Moran A (2004) ZnT1 expression in astroglial cells protects against zinc toxicity and slows the accumulation of intracellular zinc. Glia 43:145–155
Nunomura A, Hofer T, Moreira PT, Castellani RJ, Smith MA, Perry G (2009) RNA oxidation in Alzheimer disease and related neurodegenerative disorders. Acta Neuropathol 118:151–166
Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427:843–848
Octave JN (2005) Alzheimer disease: cellular and molecular aspects Bull. Mem Acad R Med Belg 160:445–449
Oddo S (2008) The ubiquitin-proteasome system in Alzheimer’s disease. J Cell Mol Med 12:363–373
Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 24:1063–10670
Oikawa N, Goto M, Ikeda K, Taguchi R, Yanagisawa K (2012) The γ-secretase inhibitor DAPT increases the levels of gangliosides at neuritic terminals of differentiating PC12 cells. Neurosci Lett 525:49–53
Olkkonen VM, Béaslas O, Nissilä E (2012) Oxysterols and their cellular effectors. Biomolecules 2:76–103
Ong WY, Kim J-H, He X, Chen P, Farooqui AA, Jenner AM (2010) Changes in brain cholesterol metabolome after kainate excitotoxicity. Mol Neurobiol 41:299–313
Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, Cappai R, Masters CL, Tanzi RE, Inestrosa NC, Bush AI (2002) Metalloenzyme-like activity of Alzheimer’s disease β-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. J Biol Chem 277:40302–40308
Pál G, Vincze C, Renner É, Wappler EA, Nagy Z, Lovas G, Dobolyi A (2012) Time course, distribution and cell types of induction of transforming growth factor betas following middle cerebral artery occlusion in the rat brain. PLoS One 7, e46731
Paoletti P, Vergnano AM, Barbour B, Casado M (2009) Zinc at glutamatergic synapses. Neuroscience 158:126–136
Paudel HK, Lew J, Ali Z, Wang JH (1993) Brain proline-directed protein kinase phosphorylates Tau on sites that are abnormally phosphorylated in Tau associated with Alzheimer’s paired helical filaments. J Biol Chem 268:23512–23518
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756
Perini G, Della-Bianca V, Politi V, Della Valle G, Dal-Pra I, Rossi F, Armato U (2002) Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines. J Exp Med 195:907–918
Pettegrew JW, Panchalingam K, Hamilton RL, McClure RJ (2001) Brain membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res 26:771–782
Pfrieger FW (2003) Outsourcing in the brain do neurons depend on cholesterol delivery by astrocytes? Bioessays 25:72–78
Pimenova AA, Thathiah A, De Strooper B, Tesseur I (2014) Regulation of amyloid precursor protein processing by serotonin signaling. PLoS One 9, e87014
Poon WW, Blurton-Jones M, Tu CH, Feinberg LM, Chabrier MA, Harris JW, Jeon NL, Cotman CW (2011) β-Amyloid impairs axonal BDNF retrograde trafficking. Neurobiol Aging 32:821–833
Poon WW, Carlos AJ, Aguilar BL, Berchtold NC, Kawano CK, Zograbyan V, Yaopruke T, Shelanski M, Cotman CW (2013) Levels of soluble apolipoprotein E/amyloid-β (Aβ) complex are reduced and oligomeric Aβ increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J Biol Chem 288:16937–16948
Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113:1456–1464
Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991
Prasad AS (2009) Impact of the discovery of human zinc deficiency on health. J Am Coll Nutr 28:257–265
Pratico D, Zhukareva V, Yao Y, Uryu K, Funk CD, Lawson JA, Trojanowski JQ, Lee VM (2004) 12/15-lipoxygenase is increased in Alzheimer’s disease: possible involvement in brain oxidative stress. Am J Pathol 164:1655–1662
Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC (2009) Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 30:1026–1036
Puglielli L, Ellis BC, Saunders AJ, Kovacs DM (2003) Ceramide stabilizes β-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid β-peptide biogenesis. J Biol Chem 278:19777–19783
Purro SA, Dickins EM, Salinas PC (2012) The secreted Wnt antagonist dickkopf-1 is required for amyloid β-mediated synaptic loss. J Neurosci 32:3492–3498
Puzzo D, Privitera L, Leznik E, Fà M, Staniszewski A, Palmeri A, Arancio O (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28:14537–14545
Qiu WQ, Folstein MF (2006) Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging 27:190–198
Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344
Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS (2008) Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab 8:512–521
Ramasamy R, Yan SF, Schmidt AM (2009) RAGE therapeutic target and biomarker of the inflammatory response-the evidence mounts. J Leukoc Biol 86:505–512
Rao JS, Rapoport SI, Kim HW (2011) Altered neuroinflammatory, arachidonic acid cascade and synaptic markers in postmortem Alzheimer’s disease brain. Transl Psychiatry 1, e31
Rao JS, Keleshian VL, Klein S, Rapoport SI (2012) Epigenetic modifications in frontal cortex from Alzheimer’s disease and bipolar disorder patients. Transl Psychiatry 2, e132
Reddy PH (2009) Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer’s disease. Exp Neurol 218:286–292
Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med 14:45–53
Reddy PH, Geethalakshmi M, Byung SP, Joline J, Geoffrey M, William W Jr, Jeffrey K, Maria M (2005) Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction. J Alzheimers Dis 7:103–117
Reitz C, Mayeux R (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88:640–651
Renner M, Lacor PN, Velasco PT, Xu J, Contractor A, Klein WL, Triller A (2010) Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron 66:739–754
Reser JE (2009) Alzheimer’s disease and natural cognitive aging may represent adaptive metabolism reduction programs. Behav Brain Funct 5:13
Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R, Vitek MP, LaFerla FM, Rohn TT, Cotman CW (2004) Caspase-cleavage of Tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114:121–130
Ritter A, Cummings J (2015) Fluid biomarkers in clinical trials of Alzheimer’s disease therapeutics. Front Neurol 6:186
Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L (2007) Reducing endogenous Tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754
Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu G-Q, Palop JJ, Noebels JL, Mucke L (2011) Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on Tau levels in multiple mouse models of Alzheimer’s disease. J Neurosci 31:700–711
Robertson KD, Wolffe AP (2000) DNA methylation in health and disease. Nat Rev Genet 1:11–19
Rohan de Silva HA, Jen A, Wickenden C, Jen LS, Wilkinson SL, Patel AJ (1997) Cell-specific expression of beta-amyloid precursor protein isoform mRNAs and proteins in neurons and astrocytes. Brain Res Mol Brain Res 47:147–156
Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P, Morabito M, Almeida OF (2005) Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci 25:11061–1070
Rosso SB, Inestrosa NC (2013) WNT signaling in neuronal maturation and synaptogenesis. Front Cell Neurosci 7:103
Russell DW, Halford RW, Ramirez DM, Shah R, Kotti T (2009) Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain. Annu Rev Biochem 78:1017–1040
Sacchetti P, Sousa KM, Hall AC, Liste I, Steffensen KR, Theofilopoulos S, Parish CL, Hazenberg C, Richter LA, Hovatta O, Gustafsson JA, Arenas E (2009) Liver X receptors and oxysterols promote ventral midbrain neurogenesis in vivo and in human embryonic stem cells. Cell Stem Cell 5:409–419
Sala Frigerio C, Lau P, Salta E, Tournoy J, Bossers K, Vandenberghe R, Wallin A, Bjerke M, Zetterberg H, Blennow K, De Strooper B (2011) Reduced expression of hsa-miR27a-3p in CSF of patients with Alzheimer disease. Neurology 81:2103–2106
Santucci R, Sinibaldi F, Fiorucci L (2008) Protein folding, unfolding and misfolding: role played by intermediate states. Mini Rev Med Chem 8:57–62
Saravia FE, Revsin Y, Gonzalez Deniselle MC, Gonzalez SL, Roig P, Lima A, Homo-Delarche F, De Nicola AF (2002) Increased astrocyte reactivity in the hippocampus of murine models of type 1 diabetes: the nonobese diabetic (NOD) and streptozotocin-treated mice. Brain Res 957:345–353
Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ (2007) Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68:1501–1508
Schmidt HD, Duman RS (2007) The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol 18:391–418
Schmitt B, Bernhardt T, Moeller H-J, Heuser I, Frölich L (2004) Combination therapy in Alzheimer’s disease. CNS Drugs 18:827–844
Schmitz A, Tikkanen R, Kirfel G, Herzog V (2002) The biological role of the Alzheimer amyloid precursor protein in epithelial cells. Histochem Cell Biol 117:171–180
Schroeter ML, Stein T, Maslowski N, Neumann J (2009) Neural correlates of Alzheimer’s disease and mild cognitive impairment: a systematic and quantitative meta-analysis involving 1351 patients. Neuroimage 47:1196–1206
Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6:1054–1061
Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192:106–113
Selkoe DJ (2011) Alzheimer’s disease. Cold Spring Harb Perspect Biol 3:a004457
Seneff S, Wainwright G, Mascitelli L (2011) Nutrition and Alzheimer’s disease: the detrimental role of a high carbohydrate diet. Eur J Intern Med 22:134–140
Sethi P, Lukiw WJ (2009) Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer’s disease temporal lobe neocortex. Neurosci Lett 459:100–104
Shan X, Lin CLG (2006) Quantification of oxidized RNAs in Alzheimer’s disease. Neurobiol Aging 27:657–662
Shan X, Tashiro H, Lin CL (2003) The identification and characterization of oxidized RNAs in Alzheimer’s disease. J Neurosci 23:4913–4921
Shaw LM, Korecka M, Clark CM, Lee VM, Trojanowski JQ (2007) Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics. Nat Rev Drug Discov 6:295–303
Shelat PB, Chalimoniuk M, Wang JH, Strosznajder JB, Lee JC, Sun AY, Simonyi A, Sun GY (2008) Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A2 in cortical neurons. J Neurochem 106:45–55
Shen WX, Chen JH, Lu JH, Peng YP, Qiu YH (2014) TGF-β1 protection against Aβ1-42-induced neuroinflammation and neurodegeneration in rats. Int J Mol Sci 15:22092–22108
Shruster A, Eldar-Finkelman H, Melamed E, Offen D (2011) Wnt signaling pathway overcomes the disruption of neuronal differentiation of neural progenitor cells induced by oligomeric amyloid β-peptide. J Neurochem 116:522–529
Siegel GJ, Chauhan NB (2000) Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain. Brain Res Brain Res Rev 33:199–227
Silva-Alvarez C, Arrazola MS, Godoy JA, Ordenes D, Inestrosa NC (2013) Canonical Wnt signaling protects hippocampal neurons from Abeta oligomers: role of non-canonical Wnt-5a/Ca2+ in mitochondrial dynamics. Front Cell Neurosci 7:97
Silvestri L, Camaschella C (2008) A potential pathogenetic role of iron in Alzheimer’s disease. J Cell Mol Med 12:1548–1550
Simons K, Ikonen E (2000) How cells handle cholesterol? Science 290:1721–1726
Skovronsky DM, Moore DB, Milla ME, Doms RW, Lee VM (2000) Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network. J Biol Chem 275:2568–2575
Slutsky I, Sadeghpour S, Li B, Liu G (2004) Enhancement of synaptic plasticity through chronically reduced Ca2+ flux during uncorrelated activity. Neuron 44:835–849
Smith MA, Zhu X, Tabaton M, Liu G, McKeel DW Jr, Cohen ML, Wang X, Siedlak SL, Dwyer BE, Hayashi T, Nakamura M, Nunomura A, Perry G (2010) Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J Alzheimers Dis 19:363–372
Smith PY, Delay C, Girard J, Papon MA, Planel E, Sergeant N, Buée L, Hébert SS (2011) MicroRNA-132 loss is associated with Tau exon 10 inclusion in progressive supranuclear palsy. Hum Mol Genet 20:4016–4024
Söderberg M, Edlund C, Kristensson K, Dallner G (1991) Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids 26:421–425
Sometani A, Kataoka H, Nitta A, Fukumitsu H, Nomoto H, Furukawa S (2001) Transforming growth factor-beta1 enhances expression of brain-derived neurotrophic factor and its receptor, TrkB, in neurons cultured from rat cerebral cortex. J Neurosci Res 66:369–376
Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD (2010) The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 5, e9505
Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ (2008) β-amyloid1−42 induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28:3941–3946
Speisky H, Gomez M, Burgos-Bravo F, Lopez-Alarcon C, Jullian C, Olea-Azar C, Aliaga ME (2009) Generation of superoxide radicals by copper-glutathione complexes: redox-consequences associated with their interaction with reduced glutathione. Bioorg Med Chem 17:1803–1810
Stanyon HF, Patel K, Begum N, Viles JH (2014) Copper(II) sequentially loads onto the N-terminal amino group of the cellular prion protein before the individual octarepeats. Biochemistry 53:3934–3939
Starkov AA, Beal FM (2008) Portal to Alzheimer’s disease. Nat Med 14:1020–1021
Stephenson D, Rash K, Smalstig B, Roberts E, Johnstone E, Sharp J, Panetta J, Little S, Kramer R, Clemens J (1999) Cytosolic phospholipase A2 is induced in reactive glia following different forms of neurodegeneration. Glia 27:110–128
Stoothoff WH, Johnson GVW (2005) Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta 1739:280–297
Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, Mattson MP (2008) Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 18:1085–1088
Sultana R, Perluigi M, Butterfield DA (2009) Oxidatively modified proteins in Alzheimer’s disease (AD), mild cognitive impairment and animal models of AD: role of Abeta in pathogenesis. Acta Neuropathol 118:131–150
Sun GY, Horrocks LA, Farooqui AA (2007) The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases. J Neurochem 103:1–16
Sun GY, He Y, Chuang DY, Lee JC, Gu Z, Simonyi A, Sun AY (2012) Integrating cytosolic phospholipase A2 with oxidative/nitrosative signaling pathways in neurons: a novel therapeutic strategy for AD. Mol Neurobiol 46:85–95
Svennerholm L, Gottfries CG (1994) Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). J Neurochem 62:1039–1047
Swaminathan A, Jicha GA (2014) Nutrition and prevention of Alzheimer’s dementia. Front Aging Neurosci 6:282
Szewczyk B (2013) Zinc homeostasis and neurodegenerative disorders. Front Aging Neurosci 5:33
Tabaton M, Zhu X, Perry G, Smith MA, Giliberto L (2010) Signaling effect of amyloid-beta(42) on the processing of AbetaPP. Exp Neurol 221:18–25
Takami M, Funamoto S (2012) gamma-Secretase-dependent proteolysis of transmembrane domain of amyloid precursor protein: successive tri- and tetrapeptide release in amyloid beta-protein production. Int J Alzheimers Dis 2012, 591392
Takeda A (2000) Zinc homeostasis and functions of zinc in the brain. Biometals 14:343–351
Takeuchi M, Yamagishi S (2008) Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer’s disease. Curr Pharm Des 14:973–978
Tan Z, Shi L, Schreiber SS (2009) Differential expression of redox factor-1 associated with β-amyloid-mediated neurotoxicity. Open Neurosci J 3:26–34
Ten Dijke P, Hill CS (2004) New insights into TGF-beta-Smad signalling. Trends Biochem Sci 29:265–273
Teng J, Takei Y, Harada A, Nakata T, Chen J, Hirokawa N (2001) Synergistic effects of MAP2 and MAP1B knockout in neuronal migration, dendritic outgrowth, and microtubule organization. J Cell Biol 155:65–76
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580
Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing and function. J Biol Chem 283:29615–29619
Thounaojam MC, Kaushik DK, Basu A (2013) MicroRNAs in the brain: it’s regulatory role in neuroinflammation. Mol Neurobiol 47:1034–1044
Tian Y, Crump CJ, Li YM (2010) Dual role of alpha-secretase cleavage in the regulation of gamma-secretase activity for amyloid production. J Biol Chem 285:32549–32556
Tiffany HL, Lavigne MC, Cui YH, Wang JM, Leto TL, Gao JL, Murphy PM (2001) Amyloid-β induces chemotaxis and oxidant stress by acting at formylpeptide receptor 2 (FPR2), a G protein-coupled receptor expressed in phagocytes and brain. J Biol Chem 276:23645–23652
Tong L, Balazs R, Thornton PL, Cotman CW (2004) β-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. J Neurosci 24:6799–6809
Townsend M, Mehta T, Selkoe DJ (2007) Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 282:33305–33312
Tremblay ML, Giguere V (2008) Phosphatases at the heart of FoxO metabolic control. Cell Metab 7:101–103
Trousson A, Bernard S, Petit PX, Liere P, Pianos A, El Hadri K, Lobaccaro JM, Ghandour MS, Raymondjean M, Schumacher M, Massaad C (2009) 25-hydroxycholesterol provokes oligodendrocyte cell line apoptosis and stimulates the secreted phospholipase A2 type IIA via LXR beta and PXR. J Neurochem 109:945–958
Tyan SH, Shih AY, Walsh JJ, Maruyama H, Sarsoza F, Ku L, Eggert S, Hof PR, Koo EH, Dickstein DL (2012) Amyloid precursor protein (APP) regulates synaptic structure and function. Mol Cell Neurosci 51:43–52
Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A, Wisniewski T, Koleske AJ, Gunther EC, Nygaard HB, Strittmatter SM (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron 79:887–902
Unger J, McNeill TH, Moxley RT 3rd, White M, Moss A, Livingston JN (1989) Distribution of insulin receptor-like immunoreactivity in the rat forebrain. Neuroscience 31:143–157
Upadhya SC, Hegde AN (2007) Role of the ubiquitin proteasome system in Alzheimer’s disease. BMC Biochem 8(Suppl 1):S12
van der Heide LP, Ramakers GMJ, Smidt MP (2006) Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol 79:205–221
van Helmond Z, Miners JS, Kehoe PG, Love S (2010) Higher soluble amyloid beta concentration in frontal cortex of young adults than in normal elderly or Alzheimer’s disease. Brain Pathol 20:787–793
van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112–124
Vargas JY, Fuenzalida M, Inestrosa NC (2014) In vivo activation of Wnt signaling pathway enhances cognitive function of adult mice and reverses cognitive deficits in an Alzheimer’s disease model. J Neurosci 34:2191–2202
Vassar R (2004) BACE1: the beta-secretase enzyme in Alzheimer’s disease. J Mol Neurosci 23:105–114
Vazquez A (2013) Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases. PLoS One 8, e63822
Vega GL, Weiner MF, Lipton AM, von Bergmann K, Lutjohann D, Moore C, Svetlik D (2003) Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer disease. Arch Neurol 60:510–515
Velez-Pardo C, Garcia Ospina G, Jimenez del Rio M (2002) Aβ[25-35] peptide and iron promote apoptosis in lymphocytes by an oxidative stress mechanism: involvement of H2O2, caspase-3, NF-κB, p53 and c-Jun. Neurotoxicology 23:351–365
Verdile G, Fuller S, Atwood CS, Laws SM, Gandy SE, Martins RN (2004) The role of beta amyloid in Alzheimer’s disease: still a cause of everything or the only one who got caught? Pharmacol Res 50:397–409
Vincze C, Pál G, Wappler EA, Szabó ER, Nagy ZG, Lovas G, Dobolyi A (2010) Distribution of mRNAs encoding transforming growth factors-beta1, -2, and -3 in the intact rat brain and after experimentally induced focal ischemia. J Comp Neurol 518:3752–3770
Wagner SL, Zhang C, Cheng S, Nguyen P, Zhang X, Rynearson KD, Wang R, Li Y, Sisodia SS, Mobley WC, Tanzi RE (2014) Soluble γ-secretase modulators selectively inhibit the production of the 42-amino acid amyloid β peptide variant and augment the production of multiple carboxy-truncated amyloid β species. Biochemistry 53:702–713
Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539
Wang L-J, Colella R, Roisen FJ (1998a) Ganglioside GM1 alters neuronal morphology by modulating the association of MAP2 with microtubules and actin filaments. Brain Res Dev Brain Res 105:227–239
Wang D, Kreutzer DA, Essigmann JM (1998b) Mutagenicity and repair of oxidative DNA damage: insights from studies using defined lesions. Mutat Res 400:99–115
Wang HY, Lee DH, D’Andrea MR, Peterson PA, Shank RP, Reitz AB (2000) β-amyloid(1-42) binds to α-7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J Biol Chem 275:5626–5632
Wang Y, Kumar N, Crumbley C, Griffin PR, Burris TP (2010) A second class of nuclear receptors for oxysterols: regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol). Biochim Biophys Acta 1801:917–923
Watt NT, Taylor DR, Kerrigan TL, Griffiths HH, Rushworth JV, Whitehouse IJ, Hooper NM (2012) Prion protein facilitates uptake of zinc into neuronal cells. Nat Commun 3:1134
Wells K, Farooqui AA, Liss L, Horrocks LA (1995) Neural membrane phospholipids in Alzheimer disease. Neurochem Res 20:1329–1333
West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal aging and Alzheimer’s disease. Lancet 344:769–772
Winoto A, Littman DR (2002) Nuclear hormone receptors in T lymphocytes. Cell 109:S57–S66
Wolozin B (2004) Cholesterol and the biology of Alzheimer’s disease. Neuron 41:7–10
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol 57:1439–1443
Wyss-Coray T (2006) Tgf-Beta pathway as a potential target in neurodegeneration and Alzheimer’s. Curr Alzheimer Res 3:191–195
Xie H, Johnson GV (1997) Ceramide selectively decreases Tau levels in differentiated PC12 cells through modulation of calpain I. J Neurochem 8:1020–1030
Xie S, Xiao JX, Gong GL, Zang YF, Wang YH, Wu HK, Jiang XX (2006) Voxel-based detection of white matter abnormalities in mild Alzheimer disease. Neurology 66:1845–1849
Xu P, Guo M, Hay BA (2004) MicroRNAs and the regulation of cell death. Trends Genet 20:617–624
Xu AW, Kaelin CB, Takeda K, Akira S, Schwartz MW, Barsh GS (2005) PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115:951–958
Xu ZP, Li L, Bao J, Wang ZH, Zeng J, Liu EJ, Li XG, Huang RX, Gao D, Li MZ, Zhang Y, Liu GP, Wang JZ (2014) Magnesium protects cognitive functions and synaptic plasticity in streptozotocin-induced sporadic Alzheimer’s model. PLoS One 9, e108645
Yaar M, Zhai S, Pilch PF, Doyle SM, Eisenhauer PB, Fine RE, Gilchrest BA (1997) Binding of β-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J Clin Invest 100:2333–2340
Yaar M, Zhai S, Fine RE, Eisenhauer PB, Arble BL, Stewart KB, Gilchrest BA (2002) Amyloid β binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J Biol Chem 277:7720–7725
Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691
Yao ZX, Papadopoulos V (2002) Function of beta-amyloid in cholesterol transport: a lead to neurotoxicity. FASEB J 16:1677–1679
Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407:48–54
Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2 +) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30:11938–11950
Zha Q, Ruan Y, Hartmann T, Beyreuther K, Zhang D (2004) GM1 ganglioside regulates the proteolysis of amyloid precursor protein. Mol Psychiatry 9:946–952
Zhang Y, Schuff N, Du AT, Rosen HJ, Kramer JH, Gorno-Tempini ML, Miller BL, Weiner MW (2009) White matter damage in frontotemporal dementia and Alzheimer’s disease measured by diffusion MRI. Brain 132:2579–2592
Zhang R, Zhang Q, Niu J, Lu K, Xie B, Cui D, Xu S (2014) Screening of microRNAs associated with Alzheimer’s disease using oxidative stress cell model and different strains of senescence accelerated mice. J Neurol Sci 338:57–64
Zhao WQ, Alkon DL (2001) Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 177:125–134
Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL (1999) Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274:34893–34902
Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J 22:246–260
Zhao WQ, Lacor PN, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL (2009) Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}. J Biol Chem 284:18742–18753
Zhao W, Wu X, Xie H, Ke Y, Yung WH (2010) Permissive role of insulin in the expression of long-term potentiation in the hippocampus of immature rats. Neurosignals 18:236–245
Zhao Y, Bhattacharjee S, Jones BM, Hill J, Dua P, Lukiw WJ (2014) Regulation of neurotropic signaling by the inducible, NF-κB-sensitive miRNA-125b in Alzheimer’s disease (AD) and in primary human neuronal-glial (HNG) cells. Mol Neurobiol 50:97–106
Zhou LX, Du JT, Zeng ZY, Wu WH, Zhao YF, Kanazawa K, Ishizuka Y, Nemoto T, Nakanishi H, Li YM (2007) Copper (II) modulates in vitro aggregation of a Tau peptide. Peptides 28:2229–2234
Zhu Y, Culmsee C, Klumpp S, Krieglstein J (2004) Neuroprotection by transforming growth factor-beta1 involves activation of nuclear factor-kappaB through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinase1,2 signaling pathways. Neuroscience 123:897–906
Zhu D, Bungart BL, Yang X, Zhumadilov Z, Lee JC, Askarova S (2015) Role of membrane biophysics in Alzheimer’s-related cell pathways. Front Neurosci 9:186
Ziegenhorn AA, Schulte-Herbrüggen O, Danker-Hopfe H, Malbranc M, Hartung HD, Anders D, Lang UE, Steinhagen-Thiessen E, Schaub RT, Hellweg R (2007) Serum neurotrophins—a study on the time course and influencing factors in a large old age sample. Neurobiol Aging 28:1436–1445
Zou K, Gong JS, Yanagisawa K, Michikawa M (2002) A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci 22:4833–4841
Zuccato C, Cattaneo E (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5:311–322
Author information
Authors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Farooqui, A.A. (2016). Neurochemical Aspects of Alzheimer Disease. In: Therapeutic Potentials of Curcumin for Alzheimer Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-15889-1_1
Download citation
DOI: https://doi.org/10.1007/978-3-319-15889-1_1
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-15888-4
Online ISBN: 978-3-319-15889-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)