Abstract
Alzheimer’s disease (AD), the most common form of neuropsychiatric disorder, is characterized by neuronal degeneration and inexorably progressing dementia, especially in the elderly population. With a rapidly aging population in both developed and developing countries, AD has emerged as one of the largest growing problems worldwide. Current drugs improve the symptoms of AD, but do not have any profound intervention to delay its onset. Thus, understanding the molecular mechanisms underlying the genes tied to AD will be crucial to the development of therapeutic targets. This review will summarize the aetiology, pathology, and the evidence for the genetic components in AD, discuss the proposed amyloid cascade and the following tau hyperphosphorylation hypothesises, oxidative stress mediated neuronal cell death, as well as the function of Retromer complex during the developing of AD. Our laboratory’s current research progress and the challenges that still remained will be also highlighted.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Alzheimer A. ber einen eigenartigen schweren erkrankungsprozess der hirnrinde. Neurologisches Centralblatt, 1906, 23: 1129–1136
Graeber M B, Kosel S, Egensperger R, et al. Rediscovery of the case described by Alois Alzheimer in 1911: Historical, histological and molecular genetic analysis. Neurogenetics, 1997, 1: 73–80
Ittner L M, Gotz J. Amyloid-beta and tau—A toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci, 2011, 12: 65–72
Stefanacci R G. The costs of Alzheimer’s disease and the value of effective therapies-page 2. Am J Manag Care, 2011, 17: S356–S362
Thies W, Bleiler L. 2011 Alzheimer’s disease facts and figures. Alzheimers Dement, 2011, 7: 208–244
Zhang Y W, Thompson R, Zhang H, et al. App processing in Alzheimer’s disease. Mol Brain, 2011, 4: 3
Corder E H, Saunders A M, Strittmatter W J, et al. Gene dose of apolipoprotein e type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 1993, 261: 921–923
Blennow K, de Leon M J, Zetterberg H. Alzheimer’s disease. Lancet, 2006, 368: 387–403
Waring S C, Rosenberg R N. Genome-wide association studies in Alzheimer disease. Arch Neurol, 2008, 65: 329–334
Turner P R, O’Connor K, Tate W P, et al. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol, 2003, 70: 1–32
Priller C, Bauer T, Mitteregger G, et al. Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci, 2006, 26: 7212–7221
Zheng H, Koo E H. The amyloid precursor protein: Beyond amyloid. Mol Neurodegener, 2006, 1: 5
De Strooper B. Aph-1, pen-2, and nicastrin with presenilin generate an active gamma-secretase complex. Neuron, 2003, 38: 9–12
Hardy J, Selkoe D J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science, 2002, 297: 353–356
Wolfe M S. When loss is gain: Reduced presenilin proteolytic function leads to increased abeta42/abeta40. Talking point on the role of presenilin mutations in Alzheimer disease. EMBO Rep, 2007, 8: 136–140
Trojanowski J Q, Jedrziewski M K, Johnson B, et al. The art and science of anti-aging therapies. Sci Aging Knowledge Environ, 2005, 17: pe11
Crapper D R, Krishnan S S, Quittkat S. Aluminium, neurofibrillary degeneration and Alzheimer’s disease. J Neurol, 1976, 99: 67–80
Nie C L, Wang X S, Liu Y, et al. Amyloid-like aggregates of neuronal tau induced by formaldehyde promote apoptosis of neuronal cells. BMC Neurosci, 2007, 8: 9
He R, Lu J, Miao J. Formaldehyde stress. Sci China Life Sci, 2010, 53: 1399–1404
Wenk G L. Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry, 2003, 64(Suppl 9): 7–10
Citron M. Alzheimer’s disease: Strategies for disease modification. Nat Rev Drug Discov, 2010, 9: 387–398
O’Brien R J, Wong P C. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci, 2011, 34: 185–204
Riemenschneider M, Schoepfer-Wendels A, Friedrich P, et al. No association of vacuolar protein sorting 26 polymorphisms with Alzheimer’s disease. Neurobiol Aging, 2007, 28: 883–884
McGeer P L, McGeer E G. Nsaids and Alzheimer disease: Epidemiological, animal model and clinical studies. Neurobiol Aging, 2007, 28: 639–647
Zhang B, Carroll J, Trojanowski J Q, et al. The microtubule-stabilizing agent, epothilone d, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci, 2012, 32: 3601–3611
Mohandas E, Rajmohan V, Raghunath B. Neurobiology of Alzheimer’s disease. Indian J Psychiatry, 2009, 51: 55–61
Tanzi R E, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: A genetic perspective. Cell, 2005, 120: 545–555
Walsh D M, Selkoe D J. A beta oligomers—A decade of discovery. J Neurochem, 2007, 101: 1172–1184
You H, Tsutsui S, Hameed S, et al. Abeta neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors. Proc Natl Acad Sci USA, 2012, 109: 1737–1742
Behbehani R G. A novel method for thermodynamic study on binding of copper ion with Alzheimer’s amyliod β peptide. Chin Sci Bull, 2009, 54: 1037–1042
Loo D T, Copani A, Pike C J, et al. Apoptosis is induced by betaamyloid in cultured central nervous system neurons. Proc Natl Acad Sci USA, 1993, 90: 7951–7955
Behl C, Davis J B, Klier F G, et al. Amyloid beta peptide induces necrosis rather than apoptosis. Brain Res, 1994, 645: 253–264
Behl C, Davis J B, Lesley R, et al. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell, 1994, 77: 817–827
Hensley K, Carney J M, Mattson M P, et al. A model for betaamyloid aggregation and neurotoxicity based on free radical generation by the peptide: Relevance to Alzheimer disease. Proc Natl Acad Sci USA, 1994, 91: 3270–3274
Shearman M S, Ragan C I, Iversen L L. Inhibition of pc12 cell redox activity is a specific, early indicator of the mechanism of betaamyloid-mediated cell death. Proc Natl Acad Sci USA, 1994, 91: 1470–1474
Mattson M P, Goodman Y. Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium. Brain Res, 1995, 676: 219–224
Pillot T, Drouet B, Queille S, et al. The nonfibrillar amyloid beta-peptide induces apoptotic neuronal cell death: Involvement of its c-terminal fusogenic domain. J Neurochem, 1999, 73: 1626–1634
Vodovotz Y, Lucia M S, Flanders K C, et al. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer’s disease. J Exp Med, 1996, 184: 1425–1433
Hashimoto Y, Ito Y, Arakawa E, et al. Neurotoxic mechanisms triggered by Alzheimer’s disease-linked mutant m146l presenilin 1: Involvement of no synthase via a novel pertussis toxin target. J Neurochem, 2002, 80: 426–437
Kadowaki H, Nishitoh H, Urano F, et al. Amyloid beta induces neuronal cell death through ros-mediated ask1 activation. Cell Death Differ, 2005, 12: 19–24
Kudo W, Lee H P, Smith M A, et al. Inhibition of bax protects neuronal cells from oligomeric abeta neurotoxicity. Cell Death Dis, 2012, 3: e309
Yin G, Li L Y, Qu M, et al. Upregulation of akt attenuates amyloid-beta-induced cell apoptosis. J Alzheimers Dis, 2011, 25: 337–345
Goedert M, Spillantini M G, Jakes R, et al. Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron, 1989, 3: 519–526
Harada A, Oguchi K, Okabe S, et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature, 1994, 369: 488–491
Ishiguro K, Shiratsuchi A, Sato S, et al. Glycogen synthase kinase 3 beta is identical to tau protein kinase i generating several epitopes of paired helical filaments. FEBS Lett, 1993, 325: 167–172
Ishiguro K, Kobayashi S, Omori A, et al. Identification of the 23 kDa subunit of tau protein kinase ii as a putative activator of cdk5 in bovine brain. FEBS Lett, 1994, 342: 203–208
Avila J, Hernández F. Tau phosphorylation. In: Nixon R A, Yuan A, eds. Cytoskeleton of the Nervous System. New York: Springer, 2011. 73–82
Gotz J, Probst A, Spillantini M G, et al. Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J, 1995, 14: 1304–1313
David D C, Hauptmann S, Scherping I, et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in p301l tau transgenic mice. J Biol Chem, 2005, 280: 23802–23814
Reddy P H. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer’s disease. Brain Res, 2011, 1415: 136–148
Li H L, Wang H H, Liu S J, et al. Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer’s neurodegeneration. Proc Natl Acad Sci USA, 2007, 104: 3591–3596
Wang J Z, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol, 2008, 85: 148–175
Xiao L, Yuan Z. Redemystifying mst1/hippo signaling. Protein Cell, 2010, 1: 706–708
Lehtinen M K, Yuan Z, Boag P R, et al. A conserved mst-foxo signaling pathway mediates oxidative-stress responses and extends life span. Cell, 2006, 125: 987–1001
Jang S W, Yang S J, Srinivasan S, et al. Akt phosphorylates msti and prevents its proteolytic activation, blocking foxo3 phosphorylation and nuclear translocation. J Biol Chem, 2007, 282: 30836–30844
Yuan Z, Kim D, Shu S, et al. Phosphoinositide 3-kinase/akt inhibits mst1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem, 2010, 285: 3815–3824
Bi W, Xiao L, Jia Y, et al. C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82. J Biol Chem, 2010, 285: 6259–6264
Xiao L, Chen D, Hu P, et al. The c-abl-mst1 signaling pathway mediates oxidative stress-induced neuronal cell death. J Neurosci, 2011, 31: 9611–9619
Liu W, Wu J, Xiao L, et al. Regulation of neuronal cell death by c-abl-hippo/mst2 signaling pathway. PLoS One, 2012, 7: e36562
Belenkaya T Y, Wu Y, Tang X, et al. The retromer complex influences wnt secretion by recycling wntless from endosomes to the trans-golgi network. Dev Cell, 2008, 14: 120–131
Zhang P, Wu Y, Belenkaya T Y, et al. Snx3 controls wingless/wnt secretion through regulating retromer-dependent recycling of wntless. Cell Res, 2011, 21: 1677–1690
He X, Li F, Chang W P, et al. Gga proteins mediate the recycling pathway of memapsin 2 (bace). J Biol Chem, 2005, 280: 11696–11703
Nielsen M S, Gustafsen C, Madsen P, et al. Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor sorla. Mol Cell Biol, 2007, 27: 6842–6851
Small SA, Kent K, Pierce A, et al. Model-guided microarray implicates the retromer complex in Alzheimer’s disease. Ann Neurol, 2005, 58: 909–919
Muhammad A, Flores I, Zhang H, et al. Retromer deficiency observed in Alzheimer’s disease causes hippocampal dysfunction, neurodegeneration, and abeta accumulation. Proc Natl Acad Sci USA, 2008, 105: 7327–7332
Harterink M, Port F, Lorenowicz M J, et al. A snx3-dependent retromer pathway mediates retrograde transport of the wnt sorting receptor wntless and is required for wnt secretion. Nat Cell Biol, 2011, 13: 914–923
Vardarajan B N, Bruesegem S Y, Harbour M E, et al. Identification of Alzheimer disease-associated variants in genes that regulate retromer function. Neurobiol Aging, 2012, 33: 2231. e15–2231. e30
Choy R W, Cheng Z, Schekman R. Amyloid precursor protein (app) traffics from the cell surface via endosomes for amyloid beta (abeta) production in the trans-golgi network. Proc Natl Acad Sci USA, 2012, 109: E2077–2082
Sullivan CP, Jay A G, Stack E C, et al. Retromer disruption promotes amyloidogenic app processing. Neurobiol Dis, 2011, 43: 338–345
Okada H, Zhang W, Peterhoff C, et al. Proteomic identification of sorting nexin 6 as a negative regulator of bace1-mediated app processing. FASEB J, 2010, 24: 2783–2794
Finan G M, Okada H, Kim T W. Bace1 retrograde trafficking is uniquely regulated by the cytoplasmic domain of sortilin. J Biol Chem, 2011, 286: 12602–12616
Ranganathan S, Noyes N C, Migliorini M, et al. Lrad3, a novel low-density lipoprotein receptor family member that modulates amyloid precursor protein trafficking. J Neurosci, 2011, 31: 10836–10846
Ehehalt R, Keller P, Haass C, et al. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol, 2003, 160: 113–123
Tan J, Evin G. Beta-site app-cleaving enzyme 1 trafficking and Alzheimer’s disease pathogenesis. J Neurochem, 2012, 120: 869–880
Vilarino-Guell C, Wider C, Ross O A, et al. Vps35 mutations in parkinson disease. Am J Hum Genet, 2011, 89: 162–167
Zimprich A, Benet-Pages A, Struhal W, et al. A mutation in vps35, encoding a subunit of the retromer complex, causes late-onset parkinson disease. Am J Hum Genet, 2011, 89: 168–175
Hierro A, Rojas A L, Rojas R, et al. Functional architecture of the retromer cargo-recognition complex. Nature, 2007, 449: 1063–1067
Author information
Authors and Affiliations
Corresponding authors
Additional information
This article is published with open access at Springerlink.com
Rights and permissions
This article is published under an open access license. Please check the 'Copyright Information' section either on this page or in the PDF for details of this license and what re-use is permitted. If your intended use exceeds what is permitted by the license or if you are unable to locate the licence and re-use information, please contact the Rights and Permissions team.
About this article
Cite this article
Zhang, P., Adams, U. & Yuan, Z. Re-mention of an old neurodegenerative disease: Alzheimer’s disease. Chin. Sci. Bull. 58, 1731–1736 (2013). https://doi.org/10.1007/s11434-013-5673-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11434-013-5673-x