Abstract
According to the amyloid cascade hypothesis, the initial elevation of amyloid β-peptide (Aβ) level is the primary trigger of Alzheimer’s disease (AD). The steady-state levels of Aβ are determined by the balance of the production and clearance of Aβ. Ιn familial AD, an imbalance in Aβ kinetics arises from the abnormal generation of Aβ due to mutations in the secretases, which cleave Aβ from the amyloid precursor protein (APP), or in APP itself. However, the large majority of AD is sporadic AD (SAD), which lacks a strong genetic component. In SAD, inactivations of Aβ degradation systems might instead be the cause of the disease. We previously identified neprilysin (NEP) as the major Aβ-degrading enzyme. Importantly, NEP declines in the human brain with aging, which may contribute to the increased Aβ pathology. Therefore, the up-regulation of NEP activity in the brain represents a potential therapy for the prevention of AD. To that end, we recently developed a system to overexpress NEP throughout the brain using an newly designed adeno-associated viral vector carrying the NEP gene (AAV-NEP). In addition to the Aβ-degrading enzymes, we recently found that autophagy plays an important role in Aβ metabolism. Specifically, autophagy influences the intracellular sorting and secretion of Aβ. Intriguingly, autophagy deficiency induces intracellular Aβ accumulation, which enhances autophagy deficiency-induced neurodegeneration. This result indicates that intracellular Aβ might be toxic. Indeed, Aβ clearance systems are potential therapeutic targets in AD, to prevent the disease via a treatment already in early stages.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abramowski D, Rabe S, Upadhaya AR, Reichwald J, Danner S, Staab D, Capetillo-Zarate E, Yamaguchi H, Saido TC, Wiederhold KH, Thal DR, Staufenbiel M (2012) Transgenic expression of intraneuronal Abeta42 but not Abeta40 leads to cellular Abeta lesions, degeneration, and functional impairment without typical Alzheimer’s disease pathology. J Neurosci 32:1273–1283
Aits S, Jaattela M (2013) Lysosomal cell death at a glance. J Cell Sci 126:1905–1912
Akiyama H, Kondo H, Ikeda K, Kato M, Mcgeer PL (2001) Immunohistochemical localization of neprilysin in the human cerebral cortex: inverse association with vulnerability to amyloid beta-protein (Abeta) deposition. Brain Res 902:277–281
Bae SJ, Matsunaga Y, Takenaka M, Tanaka Y, Hamazaki Y, Shimizu K, Katayama I (2002) Substance P induced preprotachykinin-a mRNA, neutral endopeptidase mRNA and substance P in cultured normal fibroblasts. Int Arch Allergy Immunol 127:316–321
Barnes K, Matsas R, Hooper NM, Turner AJ, Kenny AJ (1988) 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 27:799–817
Barnes K, Turner AJ, Kenny AJ (1993) An immunoelectron microscopic study of pig substantia nigra shows co-localization of endopeptidase-24.11 with substance P. Neuroscience 53:1073–1082
Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 83:876–886
Bolos V, Grego-Bessa J, De La Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28:339–363
Cao L, Rickenbacher GT, Rodriguez S, Moulia TW, Albers MW (2012) The precision of axon targeting of mouse olfactory sensory neurons requires the BACE1 protease. Sci Rep 2:231
Carvalho KM, Franca MS, Camarao GC, Ruchon AF (1997) A new brain metalloendopeptidase which degrades the Alzheimer beta-amyloid 1-40 peptide producing soluble fragments without neurotoxic effects. Braz J Med Biol Res 30:1153–1156
Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM (2005) P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest 115:3285–3290
Cisse M, Halabisky B, Harris J, Devidze N, Dubal DB, Sun B, Orr A, Lotz G, Kim DH, Hamto P, Ho K, Yu GQ, Mucke L (2011) Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469:47–52
Deane R, Du Yan S, Submamaryan RK, Larue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9:907–913
Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, Xu F, Parisi M, Larue B, Hu HW, Spijkers P, Guo H, Song X, Lenting PJ, Van Nostrand WE, Zlokovic BV (2004) LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43:333–344
Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 118:4002–4013
Do TM, Noel-Hudson MS, Ribes S, Besengez C, Smirnova M, Cisternino S, Buyse M, Calon F, Chimini G, Chacun H, Scherrmann JM, Farinotti R, Bourasset F (2012) ABCG2- and ABCG4-mediated efflux of amyloid-beta peptide 1-40 at the mouse blood-brain barrier. J Alzheimers Dis 30:155–166
Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, Serneels L, Camacho IE, Marjaux E, Craessaerts K, Roebroek AJ, Schwake M, D’hooge R, Bach P, Kalinke U, Moechars D, Alzheimer C, Reiss K, Saftig P, De Strooper B (2005) Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 280:30797–30806
Duckworth WC (1979) Insulin degradation by liver cell membranes. Endocrinology 104:1758–1764
Duckworth WC, Bennett RG, Hamel FG (1998) Insulin degradation: progress and potential. Endocr Rev 19:608–624
Eckman EA, Reed DK, Eckman CB (2001) Degradation of the Alzheimer’s amyloid beta peptide by endothelin-converting enzyme. J Biol Chem 276:24540–24548
Eckman EA, Watson M, Marlow L, Sambamurti K, Eckman CB (2003) Alzheimer’s disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme. J Biol Chem 278:2081–2084
Elkins JS, Douglas VC, Johnston SC (2004) Alzheimer disease risk and genetic variation in ACE: a meta-analysis. Neurology 62:363–368
Ertekin-Taner N, Ronald J, Feuk L, Prince J, Tucker M, Younkin L, Hella M, Jain S, Hackett A, Scanlin L, Kelly J, Kihiko-Ehman M, Neltner M, Hersh L, Kindy M, Markesbery W, Hutton M, De Andrade M, Petersen RC, Graff-Radford N, Estus S, Brookes AJ, Younkin SG (2005) Elevated amyloid beta protein (Abeta42) and late onset Alzheimer’s disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene. Hum Mol Genet 14:447–460
Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 100:4162–4167
Fossati S, Ghiso J, Rostagno A (2012) TRAIL death receptors DR4 and DR5 mediate cerebral microvascular endothelial cell apoptosis induced by oligomeric Alzheimer’s Abeta. Cell Death Dis 3:e321
Friedrich RP, Tepper K, Ronicke R, Soom M, Westermann M, Reymann K, Kaether C, Fandrich M (2010) Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity. Proc Natl Acad Sci U S A 107:1942–1947
Ghosh AK, Brindisi M, Tang J (2012) Developing beta-secretase inhibitors for treatment of Alzheimer’s disease. J Neurochem 120(Suppl 1):71–83
Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH, Tarenflurbil Phase 3 Study G (2009) Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 302:2557–2564
Greengard P, Allen PB, Nairn AC (1999) Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23:435–447
Guy JL, Lambert DW, Warner FJ, Hooper NM, Turner AJ (2005) Membrane-associated zinc peptidase families: comparing ACE and ACE2. Biochim Biophys Acta 1751:2–8
Hama E, Shirotani K, Masumoto H, Sekine-Aizawa Y, Aizawa H, Saido TC (2001) Clearance of extracellular and cell-associated amyloid beta peptide through viral expression of neprilysin in primary neurons. J Biochem 130:721–726
Hamazaki H (1996) Cathepsin D is involved in the clearance of Alzheimer’s beta-amyloid protein. FEBS Lett 396:139–142
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356
Hedskog L, Zhang S, Ankarcrona M (2012) Strategic role for mitochondria in Alzheimer’s disease and cancer. Antioxid Redox Signal 16:1476–1491
Hemming ML, Selkoe DJ (2005) Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem 280:37644–37650
Herz J (2001) The LDL receptor gene family: (un)expected signal transducers in the brain. Neuron 29:571–581
Hitt B, Riordan SM, Kukreja L, Eimer WA, Rajapaksha TW, Vassar R (2012) beta-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J Biol Chem 287:38408–38425
Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J (2000) Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 290:150–153
Howell S, Caswell AM, Kenny AJ, Turner AJ (1993) Membrane peptidases on human osteoblast-like cells in culture: hydrolysis of calcitonin and hormonal regulation of endopeptidase-24.11. Biochem J 290(Pt 1):159–164
Hoyer D, Bell GI, Berelowitz M, Epelbaum J, Feniuk W, Humphrey PP, O’carroll AM, Patel YC, Schonbrunn A, Taylor JE et al (1995) Classification and nomenclature of somatostatin receptors. Trends Pharmacol Sci 16:86–88
Hu J, Igarashi A, Kamata M, Nakagawa H (2001) Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem 276:47863–47868
Hu X, Zhou X, He W, Yang J, Xiong W, Wong P, Wilson CG, Yan R (2010) BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci 30:8819–8829
Hu X, He W, Luo X, Tsubota KE, Yan R (2013) BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep 4:40–49
Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6:143–150
Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, Gerard C, Hama E, Lee HJ, Saido TC (2001) Metabolic regulation of brain Abeta by neprilysin. Science 292:1550–1552
Iwata N, Takaki Y, Fukami S, Tsubuki S, Saido TC (2002) Region-specific reduction of A beta-degrading endopeptidase, neprilysin, in mouse hippocampus upon aging. J Neurosci Res 70:493–500
Iwata N, Mizukami H, Shirotani K, Takaki Y, Muramatsu S, Lu B, Gerard NP, Gerard C, Ozawa K, Saido TC (2004) Presynaptic localization of neprilysin contributes to efficient clearance of amyloid-beta peptide in mouse brain. J Neurosci 24:991–998
Iwata N, Sekiguchi M, Hattori Y, Takahashi A, Asai M, Ji B, Higuchi M, Staufenbiel M, Muramatsu S, Saido TC (2013) Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice. Sci Rep 3:1472
Jedlitschky G, Grube M, Mosyagin I, Kroemer HK, Vogelgesang S (2014) Targeting CNS transporters for treatment of neurodegenerative diseases. Curr Pharm Des 20:1523–1533
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jonsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488:96–99
Kakiya N, Saito T, Nilsson P, Matsuba Y, Tsubuki S, Takei N, Nawa H, Saido TC (2012) Cell surface expression of the major amyloid-beta peptide (Abeta)-degrading enzyme, neprilysin, depends on phosphorylation by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) and dephosphorylation by protein phosphatase 1a. J Biol Chem 287:29362–29372
Kehoe PG, Russ C, Mcilory S, Williams H, Holmans P, Holmes C, Liolitsa D, Vahidassr D, Powell J, Mcgleenon B, Liddell M, Plomin R, Dynan K, Williams N, Neal J, Cairns NJ, Wilcock G, Passmore P, Lovestone S, Williams J, Owen MJ (1999) Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease. Nat Genet 21:71–72
Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales KR, Paul SM (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10:719–726
Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Bruning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J (2011) Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice. J Clin Invest 121:3924–3931
Kurochkin IV, Goto S (1994) Alzheimer’s beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett 345:33–37
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
Lipinski MM (2010) Towards the global understanding of the autophagy regulatory network. Autophagy 6:1218–1220
Liu Q, Kawai H, Berg DK (2001) beta -Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci U S A 98:4734–4739
Malfroy B, Swerts JP, Guyon A, Roques BP, Schwartz JC (1978) High-affinity enkephalin-degrading peptidase in brain is increased after morphine. Nature 276:523–526
Marr RA, Rockenstein E, Mukherjee A, Kindy MS, Hersh LB, Gage FH, Verma IM, Masliah E (2003) Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci 23:1992–1996
Masaki T (2004) Historical review: endothelin. Trends Pharmacol Sci 25:219–224
Matsas R, Fulcher IS, Kenny AJ, Turner AJ (1983) Substance P and [Leu]enkephalin are hydrolyzed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli. Proc Natl Acad Sci U S A 80:3111–3115
Mcdermott JR, Gibson AM (1997) Degradation of Alzheimer’s beta-amyloid protein by human and rat brain peptidases: involvement of insulin-degrading enzyme. Neurochem Res 22:49–56
Miller BC, Eckman EA, Sambamurti K, Dobbs N, Chow KM, Eckman CB, Hersh LB, Thiele DL (2003) Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc Natl Acad Sci U S A 100:6221–6226
Miller MC, Tavares R, Johanson CE, Hovanesian V, Donahue JE, Gonzalez L, Silverberg GD, Stopa EG (2008) Hippocampal RAGE immunoreactivity in early and advanced Alzheimer’s disease. Brain Res 1230:273–280
Nakano S, Ikata T, Kinoshita I, Kanematsu J, Yasuoka S (1999a) Characteristics of the protease activity in synovial fluid from patients with rheumatoid arthritis and osteoarthritis. Clin Exp Rheumatol 17:161–170
Nakano Y, Kondoh G, Kudo T, Imaizumi K, Kato M, Miyazaki JI, Tohyama M, Takeda J, Takeda M (1999b) Accumulation of murine amyloidbeta42 in a gene-dosage-dependent manner in PS1 ‘knock-in’ mice. Eur J Neurosci 11:2577–2581
Nakayama K, Nagase H, Koh CS, Ohkawara T (2011) gamma-Secretase-regulated mechanisms similar to notch signaling may play a role in signaling events, including APP signaling, which leads to Alzheimer’s disease. Cell Mol Neurobiol 31:887–900
Narita M, Holtzman DM, Schwartz AL, Bu G (1997) Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein. J Neurochem 69:1904–1911
Nilsson P, Saido TC (2014) Dual roles for autophagy: degradation and secretion of Alzheimer’s disease Abeta peptide. Bioessays 36:570–578
Nilsson P, Iwata N, Muramatsu S, Tjernberg LO, Winblad B, Saido TC (2010) Gene therapy in Alzheimer’s disease – potential for disease modification. J Cell Mol Med 14:741–757
Nilsson P, Loganathan K, Sekiguchi M, Matsuba Y, Hui K, Tsubuki S, Tanaka M, Iwata N, Saito T, Saido TC (2013) Abeta secretion and plaque formation depend on autophagy. Cell Rep 5:61–69.
Nilsson P, Sekiguchi M, Akagi T, Izumi S, Komori T, Hui K, Sorgjerd K, Tanaka M, Saito T, Iwata N, Saido TC (2015) Autophagy-related protein 7 deficiency in amyloid beta (Abeta) precursor protein transgenic mice decreases Abeta in the multivesicular bodies and induces Abeta accumulation in the Golgi. Am J Pathol 185:305–13
Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983–997
Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Vassar R, Disterhoft JF (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 41:27–33
Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, Rosner MR, Safavi A, Hersh LB, Selkoe DJ (1998) Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 273:32730–32738
Rajput PS, Kharmate G, Norman M, Liu SH, Sastry BR, Brunicardi CF, Kumar U (2011) Somatostatin receptor 1 and 5 double knockout mice mimic neurochemical changes of Huntington’s disease transgenic mice. PLoS One 6:e24467
Saido TC (2003) Overview-Abeta metabolism: from Alzheimer research to brain aging control. In: Saido TC (ed) Abeta metabolism and Alzheimer’s disease. Landes Bioscience, Georgetown, USA
Saito T, Iwata N, Tsubuki S, Takaki Y, Takano J, Huang SM, Suemoto T, Higuchi M, Saido TC (2005) Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat Med 11:434–439
Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, Saido TC (2011) Potent amyloidogenicity and pathogenicity of Abeta43. Nat Neurosci 14:1023–1032
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC (2014) Single app knock-in mouse models of Alzheimer’s disease. Nat Neurosci 17:661–663
Sandebring A, Welander H, Winblad B, Graff C, Tjernberg LO (2013) The pathogenic abeta43 is enriched in familial and sporadic Alzheimer disease. PLoS One 8:e55847
Sasaki H, Saito Y, Hayashi M, Otsuka K, Niwa M (1988) Nucleotide sequence of the tissue-type plasminogen activator cDNA from human fetal lung cells. Nucleic Acids Res 16:5695
Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC (2008) Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci U S A 105:5585–5590
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177
Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6:487–498
Selkoe DJ (2001) Clearing the brain’s amyloid cobwebs. Neuron 32:177–180
Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV (2000) Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106:1489–1499
Solomon B, Koppel R, Hanan E, Katzav T (1996) Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci U S A 93:452–455
Tsubuki S, Takaki Y, Saido TC (2003) Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation. Lancet 361:1957–1958
Turner AJ, Isaac RE, Coates D (2001) The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function. Bioessays 23:261–269
Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, Siegmund W, Kunert-Keil C, Walker LC, Warzok RW (2002) Deposition of Alzheimer’s beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics 12:535–541
Vogelgesang S, Warzok RW, Cascorbi I, Kunert-Keil C, Schroeder E, Kroemer HK, Siegmund W, Walker LC, Pahnke J (2004) The role of P-glycoprotein in cerebral amyloid angiopathy; implications for the early pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 1:121–125
Waksman G, Hamel E, Fournie-Zaluski MC, Roques BP (1986) Autoradiographic comparison of the distribution of the neutral endopeptidase “enkephalinase” and of mu and delta opioid receptors in rat brain. Proc Natl Acad Sci U S A 83:1523–1527
Wang TL, Chang H, Hung CR, Tseng YZ (1997) Attenuation of neutrophil and endothelial activation by intravenous morphine in patients with acute myocardial infarction. Am J Cardiol 80:1532–1535
Wang HY, Lee DH, D’andrea MR, Peterson PA, Shank RP, Reitz AB (2000) beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J Biol Chem 275:5626–5632
Wang DS, Iwata N, Hama E, Saido TC, Dickson DW (2003) Oxidized neprilysin in aging and Alzheimer’s disease brains. Biochem Biophys Res Commun 310:236–241
Welander H, Franberg J, Graff C, Sundstrom E, Winblad B, Tjernberg LO (2009) Abeta43 is more frequent than Abeta40 in amyloid plaque cores from Alzheimer disease brains. J Neurochem 110:697–706
Wirths O, Bayer TA (2012) Intraneuronal Abeta accumulation and neurodegeneration: lessons from transgenic models. Life Sci 91:1148–1152
Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513–517
Wong-Leung YL, Kenny AJ (1968) Some properties of a microsomal peptidase in rat kidney. Biochem J 110:5P
Xiong H, Callaghan D, Jones A, Bai J, Rasquinha I, Smith C, Pei K, Walker D, Lue LF, Stanimirovic D, Zhang W (2009) ABCG2 is upregulated in Alzheimer’s brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Abeta(1-40) peptides. J Neurosci 29:5463–5475
Yamada T, Kluve-Beckerman B, Liepnieks JJ, Benson MD (1995) In vitro degradation of serum amyloid A by cathepsin D and other acid proteases: possible protection against amyloid fibril formation. Scand J Immunol 41:570–574
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
Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR, Xiao Q, Hsu FF, Turk JW, Xu J, Hsu CY, Holtzman DM, Lee JM (2006) Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 281:24566–24574
Yasojima K, Akiyama H, Mcgeer EG, Mcgeer PL (2001a) Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci Lett 297:97–100
Yasojima K, Mcgeer EG, Mcgeer PL (2001b) Relationship between beta amyloid peptide generating molecules and neprilysin in Alzheimer disease and normal brain. Brain Res 919:115–121
Zou K, Yamaguchi H, Akatsu H, Sakamoto T, Ko M, Mizoguchi K, Gong JS, Yu W, Yamamoto T, Kosaka K, Yanagisawa K, Michikawa M (2007) Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (Abeta(1-42)) to Abeta(1-40), and its inhibition enhances brain Abeta deposition. J Neurosci 27:8628–8635
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Japan
About this chapter
Cite this chapter
Hashimoto, S., Nilsson, P., Saido, T.C. (2015). Catabolism and Anabolism of Amyloid-β. In: Mori, N., Mook-Jung, I. (eds) Aging Mechanisms. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55763-0_19
Download citation
DOI: https://doi.org/10.1007/978-4-431-55763-0_19
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-55762-3
Online ISBN: 978-4-431-55763-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)