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Amyloid and Alzheimer's Disease: Inside and Out

Published online by Cambridge University Press:  02 December 2014

Joshua H. K. Tam
Affiliation:
J. Allyn Taylor Centre for Cell Biology, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada
Stephen H. Pasternak*
Affiliation:
J. Allyn Taylor Centre for Cell Biology, University of Western Ontario, London, Ontario, Canada Molecular Brain Research Group, Robarts Research Institute, Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada
*
Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada, N6A 5K8. Email: [email protected].
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Abstract

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Alzheimer's disease (AD) is poised to become the most serious healthcare issue of our generation. The leading theory of AD pathophysiology is the Amyloid Cascade Hypothesis, and clinical trials are now proceeding based on this hypothesis. Here, we review the original evidence for the Amyloid Hypothesis, which was originally focused on the extracellular deposition of beta amyloid peptides (Aβ) in large fibrillar aggregates, as well as how this theory has been extended in recent years to focus on highly toxic small soluble amyloid oligomers. We will also examine emerging evidence that Aβ may actually begin to accumulate intracellularly in lysosomes, and the role for intracellular Aβ and lysosomal dysfunction may play in AD pathophysiology. Finally, we will review the clinical implications of these findings.

Type
Review Article
Copyright
Copyright © The Canadian Journal of Neurological 2012

References

1Hebert, LE, Scherr, PA, Beckett, LA, et al.Age-specific incidence of Alzheimer’s disease in a community population. JAMA. 1995; 273(17):13549.CrossRefGoogle Scholar
2Jorm, AF.Cross-national comparisons of the occurrence of Alzheimer’s and vascular dementias. Eur Arch Psychiatry Clin Neurosci. 1991;240(4-5):21822.Google Scholar
3Smetanin, P, Lobak, P, Stiff, D, Sherman, G, Ahmad, S.Rising tide: the impact of demetia in Canada 2008-2038. Report by RiskAnalytica; 2009 [Cited Nov 8 2011; Available from: http://www.alzheimer.ca/english/rising_tide/rising_tide_report.htmGoogle Scholar
4Hebert, LE, Scherr, PA, Bienias, JL, Bennett, DA, Evans, DA.Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003 Aug;60(8):111922.Google Scholar
5Mebane-Sims, I, Association As. 2009 Alzheimer’s disease facts and figures. Alzheimers Dement. 2009 May;5(3):23470.Google Scholar
6International AsD. 2009. World Alzheimer Report 2009 [cited Nov 8 2011; Available from: http://www.alz.org/national/documents/report_full_2009worldalzheimerreport.pdfGoogle Scholar
7Nelson, PT, Braak, H, Markesbery, WR.Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol. 2009 Jan;68(1):114.CrossRefGoogle ScholarPubMed
8Selkoe, DJ.Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann NY Acad Sci. 2000;924:1725.Google Scholar
9Golde, TE.The Abeta hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease. Brain Pathol. 2005 Jan;15(1):847.Google Scholar
10Hussain, I, Powell, D, Howlett, DR, et al.Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci. 1999;14(6):41927.CrossRefGoogle ScholarPubMed
11Vassar, R, Bennett, BD, Babu-Khan, S, et al.Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286(5440):73541.Google Scholar
12Yan, R, Bienkowski, MJ, Shuck, ME, et al.Membrane-anchored aspartyl protease with Alzheimer’s disease beta- secretase activity. Nature. 1999;402(6761):5337.Google Scholar
13Sinha, S, Anderson, JP, Barbour, R, et al.Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999;402(6761):53740.Google Scholar
14Lin, X, Koelsch, G, Wu, S, Downs, D, Dashti, A, Tang, J.Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA. 2000 Feb 15;97(4):145660.Google Scholar
15Kao, SC, Krichevsky, AM, Kosik, KS, Tsai, LH.BACE1 suppression by RNA interference in primary cortical neurons. J Biol Chem. 2004 Jan 16;279(3):19429.Google Scholar
16Allinson, TM, Parkin, ET, Turner, AJ, Hooper, NM.ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res. 2003 Nov 1;74(3):34252.Google Scholar
17Koike, H, Tomioka, S, Sorimachi, H, et al.Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein. Biochem J. 1999;343 Pt 2:3715.Google Scholar
18Lammich, S, Kojro, E, Postina, R, et al.Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA. 1999;96(7):39227.CrossRefGoogle ScholarPubMed
19Sinha, S, Lieberburg, I.Cellular mechanisms of beta-amyloid production and secretion. Proc Natl Acad Sci USA. 1999 Sep 28; 96(20):1104953.Google Scholar
20Kayed, R, Head, E, Thompson, JL, et al.Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003 Apr 18;300(5618):4869.Google Scholar
21Glabe, CG.Structural classification of toxic amyloid oligomers. J Biol Chem. 2008 Oct 31;283(44):2963943.CrossRefGoogle ScholarPubMed
22Querfurth, HW, LaFerla, FM.Alzheimer’s disease. N Engl J Med. 2010 Jan 28;362(4):32944.CrossRefGoogle ScholarPubMed
23Ellis, WG, McCulloch, JR, Corley, CL.Presenile dementia in Down’s syndrome. Ultrastructural identity with Alzheimer’s disease. Neurology. 1974 Feb;24(2):1016.Google Scholar
24Wisniewski, KE, Wisniewski, HM, Wen, GY.Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol. 1985 Mar;17(3):27882.Google Scholar
25Glenner, GG, Wong, CW.Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984 Aug 16;122(3): 11315.Google Scholar
26Masters, CL, Simms, G, Weinman, NA, Multhaup, G, McDonald, BL, Beyreuther, K.Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA. 1985 Jun;82(12): 42459.Google Scholar
27Tanzi, RE, Gusella, JF, Watkins, PC, et al.Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987 Feb 20;235(4791):8804.Google Scholar
28Kang, J, Lemaire, HG, Unterbeck, A, et al.The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):7336.Google Scholar
29Haass, C, Schlossmacher, MG, Hung, AY, et al.Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature. 1992 Sep 24;359(6393):3225.Google Scholar
30Seubert, P, Vigo-Pelfrey, C, Esch, F, et al.Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature. 1992 Sep 24;359(6393):3257.Google Scholar
31Shoji, M, Golde, TE, Ghiso, J, et al.Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992;258(5079):1269.Google Scholar
32Cirrito, JR, Kang, JE, Lee, J, et al.Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008 Apr 10;58(1):4251.Google Scholar
33Cirrito, JR, Yamada, KA, Finn, MB, et al.Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):91322.Google Scholar
34Bateman, RJ, Munsell, LY, Morris, JC, Swarm, R, Yarasheski, KE, Holtzman, DM.Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006 Jul;12(7):85661.CrossRefGoogle Scholar
35Mullan, M, Crawford, F, Axelman, K, et al.A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992 Aug;1(5):3457.Google Scholar
36Goate, A, Chartier-Harlin, MC, Mullan, M, et al.Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991 Feb 21.;349(6311):7046.Google Scholar
37Eckman, CB, Mehta, ND, Crook, R, et al.A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet. 1997 Nov;6(12):20879.Google Scholar
38Hendriks, L, van Duijn, CM, Cras, P, et al.Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992 Jun;1(3):21821.Google Scholar
39Cheng, IH, Palop, JJ, Esposito, LA, Bien-Ly, N, Yan, F, Mucke, L.Aggressive amyloidosis in mice expressing human amyloid peptides with the Arctic mutation. Nat Med. 2004 Nov;10(11): 11902.CrossRefGoogle ScholarPubMed
40Nilsberth, C, Westlind-Danielsson, A, Eckman, CB, et al.The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):88793.Google Scholar
41Van Nostrand, WE, Melchor, JP, Cho, HS, Greenberg, SM, Rebeck, GW.Pathogenic effects of D23N Iowa mutant amyloid beta - protein. J Biol Chem. 2001 Aug 31;276(35):328606.Google Scholar
42Theuns, J, Brouwers, N, Engelborghs, S, et al.Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. Am J Hum Genet. 2006 Jun;78(6):93646.Google Scholar
43Rovelet-Lecrux, A, Hannequin, D, Raux, G, et al.APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006 Jan; 38(1):246.Google Scholar
44Cabrejo, L, Guyant-Marechal, L, Laquerriere, A, et al.Phenotype associated with APP duplication in five families. Brain. 2006 Nov;129(Pt 11):296676.Google Scholar
45Sleegers, K, Brouwers, N, Gijselinck, I, et al.APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain. 2006 Nov;129(Pt 11): 297783.Google Scholar
46Sherrington, R, Rogaev, EI, Liang, Y, et al.Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature. 1995;375(6534):75460.CrossRefGoogle ScholarPubMed
47Rogaev, EI, Sherrington, R, Rogaeva, EA, et al.Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature. 1995;376(6543):7758.Google Scholar
48Levy-Lahad, E, Wasco, W, Poorkaj, P, et al.Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 1995 Aug 18;269(5226):9737.Google Scholar
49Butler, R, Beattie, BL, Thong, UP, et al.A novel PS1 gene mutation in a large Aboriginal kindred. Can J Neurol Sci. 2010 May;37 (3):35964.Google Scholar
50Yu, G, Nishimura, M, Arawaka, S, et al.Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 2000;407(6800):4854.CrossRefGoogle ScholarPubMed
51Lee, SF, Shah, S, Li, H, Yu, C, Han, W, Yu, G.Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J Biol Chem. 2002 Nov 22;277(47):4501319.Google Scholar
52Francis, R, McGrath, G, Zhang, J, et al.aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell. 2002 Jul;3(1):8597.Google Scholar
53Steiner, H, Winkler, E, Edbauer, D, et al.PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. J Biol Chem. 2002 Oct 18;277(42):390625.Google Scholar
54Kimberly, WT, LaVoie, MJ, Ostaszewski, BL, Ye, W, Wolfe, MS, Selkoe, DJ.Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci USA. 2003 May 27;100(11):63827.Google Scholar
55Edbauer, D, Winkler, E, Regula, JT, Pesold, B, Steiner, H, Haass, C.Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003 May;5(5):4868.Google Scholar
56Ahn, K, Shelton, CC, Tian, Y, et al.Activation and intrinsic gammasecretase activity of presenilin 1. Proc Natl Acad Sci USA. 2010 Dec 14;107(50):2143540.CrossRefGoogle ScholarPubMed
57Kimberly, WT, Xia, W, Rahmati, T, Wolfe, MS, Selkoe, DJ.The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J Biol Chem. 2000;275(5):31738.Google Scholar
58Evin, G, Sharples, RA, Weidemann, A, et al.Aspartyl protease inhibitor pepstatin binds to the presenilins of Alzheimer’s disease. Biochemistry. 2001 Jul 27;40(28):835968.Google Scholar
59Seiffert, D, Bradley, JD, Rominger, CM, et al.Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors. J Biol Chem. 2000;275(44):3408691.Google Scholar
60Horaitis, O, Talbot, CC Jr., Phommarinh, M, Phillips, KM, Cotton, RG.A database of locus-specific databases. Nat Genet. 2007 Apr;39(4):425.Google Scholar
61Wolfe, MS.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 Feb;8(2):13640.Google Scholar
62Murayama, O, Tomita, T, Nihonmatsu, N, et al.Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer’s disease. Neurosci Lett. 1999 Apr 9;265 (1):613.Google Scholar
63Shimojo, M, Sahara, N, Murayama, M, Ichinose, H, Takashima, A.Decreased Abeta secretion by cells expressing familial Alzheimer’s disease-linked mutant presenilin 1. Neurosci Res. 2007 Mar;57(3):44653.Google Scholar
64Duering, M, Grimm, MO, Grimm, HS, Schroder, J, Hartmann, T.Mean age of onset in familial Alzheimer’s disease is determined by amyloid beta 42. Neurobiol Aging. 2005 Jun;26(6):7858.Google Scholar
65Kim, J, Basak, JM, Holtzman, DM.The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009 Aug 13;63(3):287303.Google Scholar
66Corder, EH, Saunders, AM, Risch, NJ, et al.Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994 Jun;7(2):1804.Google Scholar
67Wisniewski, T, Castano, EM, Golabek, A, Vogel, T, Frangione, B.Acceleration of Alzheimer’s fibril formation by apolipoprotein E in vitro. Am J Pathol. 1994 Nov;145(5):10305.Google Scholar
68Ma, J, Yee, A, Brewer, HB Jr., Das, S, Potter, H.Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature. 1994 Nov 3;372(6501):924.Google Scholar
69Holtzman, DM, Bales, KR, Tenkova, T, et al.Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2000;97(6):28927.Google Scholar
70Schmechel, DE, Saunders, AM, Strittmatter, WJ, et al.Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Oct 15;90 (20):964953.CrossRefGoogle ScholarPubMed
71Castellano, JM, Kim, J, Stewart, FR, et al.Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med. 2011 Jun 29;3(89):89ra57.Google Scholar
72Gatz, M, Reynolds, CA, Fratiglioni, L, et al.Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006 Feb;63(2):16874.Google Scholar
73Bertram, L, Lill, CM, Tanzi, RE.The genetics of Alzheimer disease: back to the future. Neuron. 2010 Oct 21;68(2):27081.Google Scholar
74Hollingworth, P, Harold, D, Sims, R, et al.Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011 May;43 (5):42935.Google Scholar
75Naj, AC, Jun, G, Beecham, GW, et al.Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet. 2011 May;43(5): 43641.Google Scholar
76Belbin, O, Carrasquillo, MM, Crump, M, et al.Investigation of 15 of the top candidate genes for late-onset Alzheimer’s disease. Hum Genet. 2011 Mar;129(3):27382.Google Scholar
77Bertram, L, Tanzi, RE.Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci. 2008 Oct;9(10):76878.CrossRefGoogle ScholarPubMed
78Gomez-Isla, T, Hollister, R, West, H, et al.Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997 Jan;41(1):1724.Google Scholar
79Ballatore, C, Lee, VM, Trojanowski, JQ.Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007 Sep;8(9):66372.Google Scholar
80Jacobsen, JS, Wu, CC, Redwine, JM, et al.Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2006 Mar 28;103(13):51616.Google Scholar
81Braak, H, Braak, E.Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):23959.Google Scholar
82van Swieten, J, Spillantini, MG.Hereditary frontotemporal dementia caused by Tau gene mutations. Brain Pathol. 2007 Jan;17(1): 6373.Google Scholar
83Lemere, CA, Blusztajn, JK, Yamaguchi, H, Wisniewski, T, Saido, TC, Selkoe, DJ.Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996 Feb;3(1):1632.Google Scholar
84Oddo, S, Caccamo, A, Tran, L, et al.Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem. 2006 Jan 20;281(3):1599604.Google Scholar
85Lewis, J, Dickson, DW, Lin, WL, et al.Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001 Aug 24;293(5534):148791.Google Scholar
86Gotz, J, Chen, F, van Dorpe, J, Nitsch, RM.Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001 Aug 24;293(5534):14915.Google Scholar
87Oddo, S, Billings, L, Kesslak, JP, Cribbs, DH, LaFerla, FM.Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron. 2004 Aug 5;43(3):32132.Google Scholar
88Bolmont, T, Clavaguera, F, Meyer-Luehmann, M, et al.Induction of tau pathology by intracerebral infusion of amyloid-beta - containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am J Pathol. 2007 Dec;171(6):201220.Google Scholar
89Santacruz, K, Lewis, J, Spires, T, et al.Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005 Jul 15;309(5733):47681.Google Scholar
90Roberson, ED, Scearce-Levie, K, Palop, JJ, et al.Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science. 2007 May 4;316 (5825):7504.Google Scholar
91Ittner, LM, Ke, YD, Delerue, F, et al.Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell. 2010 Aug 6;142(3):38797.Google Scholar
92Terry, RD, Masliah, E, Salmon, DP, et al.Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991 Oct;30(4): 57280.Google Scholar
93Scheff, SW, Price, DA.Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging. 2003 Dec;24 (8):102946.Google Scholar
94Scheff, SW, Price, DA, Schmitt, FA, DeKosky, ST, Mufson, EJ.Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology. 2007 May 1;68(18):15018.Google Scholar
95Selkoe, DJ.Alzheimer’s disease is a synaptic failure. Science. 2002 Oct 25;298(5594):78991.Google Scholar
96Naslund, J, Haroutunian, V, Mohs, R, et al.Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000 Mar 22-29;283(12):15717.Google Scholar
97Lue, LF, Kuo, YM, Roher, AE, et al.Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol. 1999 Sep;155(3):85362.Google Scholar
98Walsh, DM, Selkoe, DJ.A beta oligomers - a decade of discovery. J Neurochem. 2007 Jun;101(5):117284.Google Scholar
99Lacor, PN, Buniel, MC, Furlow, PW, et al.Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci. 2007 Jan 24;27(4):796807.Google Scholar
100Lesne, S, Koh, MT, Kotilinek, L, et al.A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):3527.Google Scholar
101Shankar, GM, Li, S, Mehta, TH, et al.Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008 Aug;14(8):83742.Google Scholar
102Cleary, JP, Walsh, DM, Hofmeister, JJ, et al.Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci. 2005 Jan;8(1):7984.Google Scholar
103Shankar, GM, Bloodgood, BL, Townsend, M, Walsh, DM, Selkoe, DJ, Sabatini, BL.Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007 Mar 14;27(11):286675.Google Scholar
104Dodart, JC, Bales, KR, Gannon, KS, et al.Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci. 2002 May;5(5):4527.Google Scholar
105Balducci, C, Beeg, M, Stravalaci, M, et al.Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci USA. 2010 Feb 2;107(5): 2295300.CrossRefGoogle ScholarPubMed
106Bell, KF, Ducatenzeiler, A, Ribeiro-da-Silva, A, Duff, K, Bennett, DA, Cuello, AC.The amyloid pathology progresses in a neurotransmitter-specific manner. Neurobiol Aging. 2006 Nov; 27(11):164457.Google Scholar
107Renner, M, Lacor, PN, Velasco, PT, et al.Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron. Jun 10;66(5):73954.Google Scholar
108Parodi, J, Sepulveda, FJ, Roa, J, Opazo, C, Inestrosa, NC, Aguayo, LG.Beta-amyloid causes depletion of synaptic vesicles leading to neurotransmission failure. J Biol Chem. Jan 22;285(4):250614.Google Scholar
109Lauren, J, Gimbel, DA, Nygaard, HB, Gilbert, JW, Strittmatter, SM.Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009 Feb 26;457(7233): 112832.Google Scholar
110Barry, AE, Klyubin, I, Mc Donald, JM, et al.Alzheimer’s disease brain-derived amyloid-beta-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci. 2011 May 18;31(20):725963.Google Scholar
111Gimbel, DA, Nygaard, HB, Coffey, EE, et al.Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci. 2010 May 5;30(18):636774.Google Scholar
112Calella, AM, Farinelli, M, Nuvolone, M, et al.Prion protein and Abeta-related synaptic toxicity impairment. EMBO Mol Med. Aug;2(8):30614.Google Scholar
113Dunn, WA Jr. Studies on the mechanisms of autophagy: maturation of the autophagic vacuole. J Cell Biol. 1990 Jun;110(6):193545.Google Scholar
114Dunn, WA Jr. Studies on the mechanisms of autophagy: formation of the autophagic vacuole. J Cell Biol. 1990 Jun;110(6):192333.Google Scholar
115Nixon, RA, Cataldo, AM, Mathews, PM.The endosomal-lysosomal system of neurons in Alzheimer’s disease pathogenesis: a review. Neurochem Res. 2000;25(9-10):116172.Google Scholar
116Eskelinen, EL, Tanaka, Y, Saftig, P.At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 2003 Mar;13(3):13745.Google Scholar
117Sachse, M, Ramm, G, Strous, G, Klumperman, J.Endosomes: multipurpose designs for integrating housekeeping and specialized tasks. Histochem Cell Biol. 2002 Feb;117(2):91104.Google Scholar
118Pillay, CS, Elliott, E, Dennison, C.Endolysosomal proteolysis and its regulation. Biochem J. 2002 May 1;363(Pt 3):41729.Google Scholar
119Li, AX, Hudson, RHE, Barrett, JW, Jones, CK, Pasternak, SH, Bartha, R.Four-pool modeling of proton exchange processes in biological systems in the presence of MRI-paramagnetic chemical exchange saturation transfer (PARACEST) agents. Magn Reson Med. 2008;60(5):1197206.Google Scholar
120Jaiswal, JK, Andrews, NW, Simon, SM.Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells. J Cell Biol. 2002 Nov 25;159(4):62535.Google Scholar
121Stinchcombe, JC, Griffiths, GM.Regulated secretion from hemopoietic cells. J Cell Biol. 1999 Oct 4;147(1):16.Google Scholar
122Andrews, NW.Regulated secretion of conventional lysosomes. Trends Cell Biol. 2000;10(8):31621.Google Scholar
123Reddy, A, Caler, EV, Andrews, NW.Plasma membrane repair is mediated by Ca(2+)-regulated exocytosis of lysosomes. Cell. 2001;106(2):15769.Google Scholar
124Haass, C, Koo, EH, Mellon, A, Hung, AY, Selkoe, DJ.Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature. 1992;357(6378):5003.Google Scholar
125Koo, EH, Squazzo, SL.Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem. 1994;269(26):173869.Google Scholar
126Koo, EH, Squazzo, SL, Selkoe, DJ, Koo, CH.Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody. J Cell Sci. 1996;109(Pt 5):9918.Google Scholar
127Yamazaki, T, Koo, EH, Selkoe, DJ.Trafficking of cell-surface amyloid beta-protein precursor. II. Endocytosis, recycling and lysosomal targeting detected by immunolocalization. J Cell Sci. 1996;109(Pt 5):9991008.Google Scholar
128Jung, SS, Cashman, NR.Processing of the beta-amyloid precursor protein in ex vivo human brain cells. Neuroreport. 1999;10(18): 38759.Google Scholar
129Grbovic, OM, Mathews, PM, Jiang, Y, et al.Rab5-stimulated up-regulation of the endocytic pathway increases intracellular beta-cleaved amyloid precursor protein carboxyl-terminal fragment levels and Abeta production. J Biol Chem. 2003 Aug 15;278 (33):312618.Google Scholar
130Colombo, A, Bastone, A, Ploia, C, et al.JNK regulates APP cleavage and degradation in a model of Alzheimer’s disease. Neurobiol Dis. 2009 Mar;33(3):51825.Google Scholar
131Vieira, SI, Rebelo, S, Domingues, SC, da Cruz e Silva, EF, da Cruz e Silva, OA.S655 phosphorylation enhances APP secretory traffic. Mol Cell Biochem. 2009 Aug;328(1-2):14554.Google Scholar
132Rebelo, S, Vieira, SI, Esselmann, H, Wiltfang, J, da Cruz e Silva, EF, da Cruz e Silva, OA.Tyr687 dependent APP endocytosis and Abeta production. J Mol Neurosci. 2007;32(1):18.Google Scholar
133Rebelo, S, Vieira, SI, Esselmann, H, Wiltfang, J, da Cruz e Silva, EF, da Cruz e Silva, OA.Tyrosine 687 phosphorylated Alzheimer’s amyloid precursor protein is retained intracellularly and exhibits a decreased turnover rate. Neurodegener Dis. 2007;4(2-3):7887.Google Scholar
134Suzuki, T, Nakaya, T.Regulation of amyloid beta-protein precursor by phosphorylation and protein interactions. J Biol Chem. 2008 Oct 31;283(44):296337.Google Scholar
135Schobel, S, Neumann, S, Hertweck, M, et al.A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein. J Biol Chem. 2008 May 23;283 (21):1425768.Google Scholar
136Schobel, S, Neumann, S, Seed, B, Lichtenthaler, SF.Expression cloning screen for modifiers of amyloid precursor protein shedding. Int J Dev Neurosci. 2006 Apr-May;24(2-3):1418.Google Scholar
137Miller, CC, McLoughlin, DM, Lau, KF, Tennant, ME, Rogelj, B.The X11 proteins, Abeta production and Alzheimer’s disease. Trends Neurosci. 2006 May;29(5):2805.Google Scholar
138Yu, WH, Cuervo, AM, Kumar, A, et al.Macroautophagy-a novel {beta}-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol. 2005 Oct 10;171(1):8798.Google Scholar
139Yu, WH, Kumar, A, Peterhoff, C, et al.Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer’s disease. Int J Biochem Cell Biol. 2004 Dec;36(12):253140.Google Scholar
140Bagshaw, RD, Pasternak, SH, Mahuran, DJ, Callahan, JW.Nicastrin is a resident lysosomal membrane protein. Biochem Biophys Res Commun. 2003 Jan 17;300(3):61518.Google Scholar
141Pasternak, SH, Bagshaw, RD, Guiral, M, et al.Presenilin-1, nicastrin, amyloid precursor protein, and gamma-secretase activity are colocalized in the lysosomal membrane. J Biol Chem. 2003 Jul 18; 278(29):2668794.Google Scholar
142Lorenzen, A, Samosh, J, Vandewark, K, et al.Rapid and direct transport of cell surface APP to the lysosome defines a novel selective pathway. Mol Brain. 2010;3:11.Google Scholar
143Pasternak, SH, Callahan, JW, Mahuran, DJ.The role of the endosomal/lysosomal system in amyloid-beta production and the pathophysiology of Alzheimer’s disease: reexamining the spatial paradox from a lysosomal perspective. J Alzheimers Dis. 2004 Feb;6(1):5365.Google Scholar
144Turner, RS, Suzuki, N, Chyung, AS, Younkin, SG, Lee, VM.Amyloids beta40 and beta42 are generated intracellularly in cultured human neurons and their secretion increases with maturation. J Biol Chem. 1996;271(15):896670.Google Scholar
145Wertkin, AM, Turner, RS, Pleasure, SJ, et al.Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides. Proc Natl Acad Sci USA. 1993 Oct 15; 90(20):951317.Google Scholar
146Martin, BL, Schrader-Fischer, G, Busciglio, J, Duke, M, Paganetti, P, Yankner, BA.Intracellular accumulation of beta-amyloid in cells expressing the Swedish mutant amyloid precursor protein. J Biol Chem. 1995 Nov 10;270(45):2672730.Google Scholar
147Skovronsky, DM, Doms, RW, Lee, VM.Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture. J Cell Biol. 1998 May 18;141 (4):10319.Google Scholar
148Walsh, DM, Tseng, BP, Rydel, RE, Podlisny, MB, Selkoe, DJ.The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry. 2000;39(35): 108319.Google Scholar
149D’Andrea, MR, Nagele, RG, Wang, HY, Peterson, PA, Lee, DH.Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer’s disease. Histopathology. 2001;38(2):12034.Google Scholar
150D’Andrea, MR, Reiser, PA, Polkovitch, DA, et al.The use of formic acid to embellish amyloid plaque detection in Alzheimer’s disease tissues misguides key observations. Neurosci Lett. 2003 May 15;342(1-2):11418.Google Scholar
151D’Andrea, MR, Nagele, RG, Wang, HY, Lee, DH.Consistent immunohistochemical detection of intracellular beta-amyloid42 in pyramidal neurons of Alzheimer’s disease entorhinal cortex. Neurosci Lett. 2002 Nov 29;333(3):1636.Google Scholar
152Aho, L, Pikkarainen, M, Hiltunen, M, Leinonen, V, Alafuzoff, I.Immunohistochemical visualization of amyloid-beta protein precursor and amyloid-beta in extra- and intracellular compartments in the human brain. J Alzheimers Dis. 2010;20(4): 101528.Google Scholar
153Gouras, GK, Tampellini, D, Takahashi, RH, Capetillo-Zarate, E.Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta Neuropathol. 2010 May;119(5): 52341.Google Scholar
154Winton, MJ, Lee, EB, Sun, E, et al.Intraneuronal APP, not free Abeta peptides in 3xTg-AD mice: implications for tau versus Abeta-mediated Alzheimer neurodegeneration. J Neurosci. 2011 May 25;31(21):76919.Google Scholar
155Glabe, C.Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J Mol Neurosci. 2001 Oct; 17(2):13745.Google Scholar
156Gouras, GK, Almeida, CG, Takahashi, RH.Intraneuronal Abeta accumulation and origin of plaques in Alzheimer’s disease. Neurobiol Aging. 2005 Oct;26(9):123544.Google Scholar
157LaFerla, FM, Green, KN, Oddo, S.Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci. 2007 Jul;8(7):499509.Google Scholar
158Chui, DH, Tanahashi, H, Ozawa, K, et al.Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med. 1999 May;5(5):5604.Google Scholar
159Shie, FS, LeBoeur, RC, Jin, LW.Early intraneuronal Abeta deposition in the hippocampus of APP transgenic mice. Neuroreport. 2003 Jan 20;14(1):1239.Google Scholar
160Wirths, O, Multhaup, G, Czech, C, et al.Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neurosci Lett. 2001 Jun 22;306(1-2):11620.Google Scholar
161Takahashi, RH, Almeida, CG, Kearney, PF, et al.Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci. 2004 Apr 7;24(14): 35929.Google Scholar
162Knobloch, M, Konietzko, U, Krebs, DC, Nitsch, RM.Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging. 2007 Sep;28(9): 1297306.Google Scholar
163Oakley, H, Cole, SL, Logan, S, et al.Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006 Oct 4;26 (40):1012940.Google Scholar
164Oddo, S, Caccamo, A, Smith, IF, Green, KN, LaFerla, FM.A dynamic relationship between intracellular and extracellular pools of Abeta. Am J Pathol. 2006 Jan;168(1):18494.Google Scholar
165Yan, P, Bero, AW, Cirrito, JR, et al.Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J Neurosci. 2009 Aug 26;29(34):1070614.Google Scholar
166Billings, LM, Oddo, S, Green, KN, McGaugh, JL, Laferla, FM.Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron. 2005 Mar 3;45(5):67588.Google Scholar
167Gouras, GK, Tsai, J, Naslund, J, et al.Intraneuronal Abeta42 accumulation in human brain. Am J Pathol. 2000;156(1):1520.CrossRefGoogle ScholarPubMed
168Gyure, KA, Durham, R, Stewart, WF, Smialek, JE, Troncoso, JC.Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch Pathol Lab Med. 2001 Apr; 125(4):48992.Google Scholar
169Cataldo, AM, Petanceska, S, Terio, NB, et al.Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome. Neurobiol Aging. 2004 Nov-Dec; 25(10):126372.Google Scholar
170LaFerla, FM, Troncoso, JC, Strickland, DK, Kawas, CH, Jay, G.Neuronal cell death in Alzheimer’s disease correlates with apoE uptake and intracellular Abeta stabilization. J Clin Invest. 1997 Jul 15;100(2):31020.Google Scholar
171Aoki, M, Volkmann, I, Tjernberg, LO, Winblad, B, Bogdanovic, N.Amyloid beta-peptide levels in laser capture microdissected cornu ammonis 1 pyramidal neurons of Alzheimer’s brain. Neuroreport. 2008 Jul 16;19(11):10859.Google Scholar
172Hashimoto, M, Bogdanovic, N, Volkmann, I, Aoki, M, Winblad, B, Tjernberg, LO.Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Abeta42 and Alzheimer’s disease neuropathology. Acta Neuropathol. 2010 May;119(5):54354.Google Scholar
173Su, Y, Chang, PT.Acidic pH promotes the formation of toxic fibrils from beta-amyloid peptide. Brain Res. 2001;893(1-2):28791.Google Scholar
174Inouye, H, Kirschner, DA.A beta fibrillogenesis: kinetic parameters for fibril formation from congo red binding. J Struct Biol. 2000 Jun;130(2-3):1239.Google Scholar
175McLaurin, J, Chakrabartty, A.Membrane disruption by Alzheimer beta-amyloid peptides mediated through specific binding to either phospholipids or gangliosides. Implications for neurotoxicity. J Biol Chem. 1996 Oct 25;271(43):264829.Google Scholar
176Waschuk, SA, Elton, EA, Darabie, AA, Fraser, PE, McLaurin, JA.Cellular membrane composition defines A beta-lipid interactions. J Biol Chem. 2001;276(36):335618.CrossRefGoogle ScholarPubMed
177Yanagisawa, K, Odaka, A, Suzuki, N, Ihara, Y.GM1 gangliosidebound amyloid beta-protein (A beta): a possible form of preamyloid in Alzheimer’s disease. Nat Med. 1995 Oct;1(10): 10626.Google Scholar
178Yip, CM, McLaurin, J.Amyloid-beta peptide assembly: a critical step in fibrillogenesis and membrane disruption. Biophys J. 2001;80(3):135971.Google Scholar
179Knauer, MF, Soreghan, B, Burdick, D, Kosmoski, J, Glabe, CG.Intracellular accumulation and resistance to degradation of the Alzheimer amyloid A4/beta protein. Proc Natl Acad Sci USA. 1992;89(16):743741.Google Scholar
180Yang, AJ, Knauer, M, Burdick, DA, Glabe, C.Intracellular A beta 1-42 aggregates stimulate the accumulation of stable, insoluble amyloidogenic fragments of the amyloid precursor protein in transfected cells. J Biol Chem. 1995 Jun 16;270(24):1478692.Google Scholar
181Yang, AJ, Chandswangbhuvana, D, Shu, T, Henschen, A, Glabe, CG.Intracellular accumulation of insoluble, newly synthesized abetan-42 in amyloid precursor protein-transfected cells that have been treated with Abeta1-42. J Biol Chem. 1999;274(29): 206506.Google Scholar
182Hu, X, Crick, SL, Bu, G, Frieden, C, Pappu, RV, Lee, JM.Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide. Proc Natl Acad Sci USA. 2009 Dec 1;106(48):203249.CrossRefGoogle ScholarPubMed
183Takahashi, RH, Milner, TA, Li, F, et al.Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol. 2002 Nov;161(5): 186979.Google Scholar
184Yang, AJ, Chandswangbhuvana, D, Margol, L, Glabe, CG.Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid Abeta1-42 pathogenesis. J Neurosci Res. 1998; 52(6):6918.3.0.CO;2-3>CrossRefGoogle ScholarPubMed
185Ji, ZS, Miranda, RD, Newhouse, YM, Weisgraber, KH, Huang, Y, Mahley, RW.Apolipoprotein E4 potentiates amyloid beta peptide-induced lysosomal leakage and apoptosis in neuronal cells. J Biol Chem. 2002 Jun 14;277(24):218218.Google Scholar
186Turk, B, Turk, V.Lysosomes as “suicide bags” in cell death: myth or reality? J Biol Chem. 2009 Aug 14;284(33):217837.Google Scholar
187Kienlen-Campard, P, Miolet, S, Tasiaux, B, Octave, JN.Intracellular amyloid-beta 1-42, but not extracellular soluble amyloid-beta peptides, induces neuronal apoptosis. J Biol Chem. 2002 May 3; 277(18):1566670.Google Scholar
188Mori, C, Spooner, ET, Wisniewsk, KE, et al.Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid. 2002 Jun;9(2): 88102.Google Scholar
189Cataldo, AM, Nixon, RA.Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc Natl Acad Sci USA. 1990 May;87(10):38615.Google Scholar
190Cataldo, AM, Paskevich, PA, Kominami, E, Nixon, RA.Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci USA. 1991 Dec 15;88(24):109981002.Google Scholar
191Cataldo, AM, Hamilton, DJ, Nixon, RA.Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease. Brain Res. 1994 Mar 21;640 (1-2):6880.Google Scholar
192Mach, L.Biosynthesis of lysosomal proteinases in health and disease. Biol Chem. 2002 May;383(5):7516.Google Scholar
193D’Andrea, M, Nagele, R.Morphologically distinct types of amyloid plaques point the way to a better understanding of Alzheimer’s disease pathogenesis. Biotech Histochem. 2010 Apr;85(2): 13347.Google Scholar
194Meyer-Luehmann, M, Spires-Jones, TL, Prada, C, et al.Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature. 2008 Feb 7;451 (7179):7204.Google Scholar
195Cataldo, AM, Barnett, JL, Pieroni, C, Nixon, RA.Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer’s disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci. 1997;17(16):614251.Google Scholar
196Cataldo, AM, Peterhoff, CM, Troncoso, JC, Gomez-Isla, T, Hyman, BT, Nixon, RA.Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer’s disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol. 2000;157(1):27786.Google Scholar
197Cataldo, AM, Peterhoff, CM, Schmidt, SD, et al.Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology. J Neuropathol Exp Neurol. 2004 Aug;63(8):82130.Google Scholar
198Nixon, RA, Wegiel, J, Kumar, A, et al.Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005 Feb;64(2): 11322.Google Scholar
199Nixon, RA, Yang, DS, Lee, JH.Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy. 2008 Jul 1;4(5):5909.Google Scholar
200Boland, B, Kumar, A, Lee, S, et al.Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci. 2008 Jul 2;28(27): 692637.Google Scholar
201Komatsu, M, Waguri, S, Chiba, T, et al.Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006 Jun 15;441(7095):8804.Google Scholar
202Yamazaki, T, Chang, TY, Haass, C, Ihara, Y.Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann-pick type C cells. J Biol Chem. 2001;276(6):445460.Google Scholar
203Boland, B, Smith, DA, Mooney, D, Jung, SS, Walsh, DM, Platt, FM.Macroautophagy is not directly involved in the metabolism of amyloid precursor protein. J Biol Chem. 2010 Nov 26;285 (48): 3741526.Google Scholar
204Ginsberg, SD, Galvin, JE, Lee, VM, et al.Accumulation of intracellular amyloid-beta peptide (A beta 1-40) in mucopolysaccharidosis brains. J Neuropathol Exp Neurol. 1999 Aug;58(8):81524.Google Scholar
205Lee, S, Sato, Y, Nixon, RA.Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy. J Neurosci. 2011 May 25;31(21):781730.CrossRefGoogle ScholarPubMed
206Tamboli, IY, Hampel, H, Tien, NT, et al.Sphingolipid storage affects autophagic metabolism of the amyloid precursor protein and promotes Abeta generation. J Neurosci. 2011 Feb 2;31(5): 183749.Google Scholar
207Zhang, M, Haapasalo, A, Kim, DY, Ingano, LA, Pettingell, WH, Kovacs, DM.Presenilin/gamma-secretase activity regulates protein clearance from the endocytic recycling compartment. FASEB J. 2006 Jun;20(8):11768.Google Scholar
208Bagshaw, R, Pasternak, S, Mahuran, D, Callahan, J.Nicastrin is a resident lysosomal membrane protein. Biochem Bioph Res Co. 2003 Jan 17 2003;300(3):61518.Google Scholar
209Neely, KM, Green, KN, LaFerla, FM.Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a gamma-secretase-independent manner. J Neurosci. 2011 Feb 23;31(8):278191.Google Scholar
210Hryciw, T, MacDonald, JIS, Phillips, R, Seah, C, Pasternak, S, Meakin, SO.The fibroblast growth factor receptor substrate 3 adapter is a developmentally regulated microtubule-associated protein expressed in migrating and differentiated neurons. J Neurochem. 2010;112(4):92439.Google Scholar
211Lee, JH, Yu, WH, Kumar, A, et al.Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010 Jun 25;141(7):114658.Google Scholar
212Yang, DS, Stavrides, P, Mohan, PS, et al.Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain. 2010 Jan;134(Pt 1):25877.Google Scholar
213Butler, D, Brown, QB, Chin, DJ, et al.Cellular responses to protein accumulation involve autophagy and lysosomal enzyme activation. Rejuvenation Res. 2005 Winter;8(4):22737.Google Scholar
214Bendiske, J, Bahr, BA.Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis-an approach for slowing Alzheimer disease? J Neuropathol Exp Neurol. 2003 May;62(5):45163.Google Scholar
215Golde, TE, Petrucelli, L, Lewis, J.Targeting Abeta and tau in Alzheimer’s disease, an early interim report. Exp Neurol. 2010 Jun;223(2):25266.Google Scholar
216Mangialasche, F, Solomon, A, Winblad, B, Mecocci, P, Kivipelto, M.Alzheimer’s disease: clinical trials and drug development. Lancet Neurol. 2010 Jul;9(7):70216.Google Scholar
217Salloway, S, Sperling, R, Gilman, S, et al.A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009 Dec 15;73(24):206170.Google Scholar
218Rinne, JO, Brooks, DJ, Rossor, MN, et al.11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010 Apr;9(4):36372.Google Scholar
219Istrin, G, Bosis, E, Solomon, B.Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-beta peptide. J Neurosci Res. 2006 Aug 1;84(2):43443.Google Scholar
220Banks, WA, Farr, SA, Morley, JE, Wolf, KM, Geylis, V, Steinitz, M.Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer’s disease: an age-related selective uptake with reversal of learning impairment. Exp Neurol. 2007 Aug;206(2):24856.Google Scholar
221Dodel, RC, Du, Y, Depboylu, C, et al.Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2004 Oct; 75(10):14724.Google Scholar
222Relkin, NR, Szabo, P, Adamiak, B, et al.18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009 Nov;30(11):172836.Google Scholar
223McLaurin, J, Kierstead, ME, Brown, ME, et al.Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006 Jul;12(7):8018.Google Scholar
224Golde, TE, Schneider, LS, Koo, EH.Anti-abeta therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron. 2011 Jan 27;69(2):20313.CrossRefGoogle ScholarPubMed
225Gilman, S, Koller, M, Black, RS, et al.Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005 May 10;64(9):155362.Google Scholar
226Nicoll, JA, Barton, E, Boche, D, et al.Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol. 2006 Nov;65 (11):10408.Google Scholar
227Sperling, RA, Aisen, PS, Beckett, LA, et al.Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 May;7(3):28092.CrossRefGoogle ScholarPubMed
228Perrin, RJ, Fagan, AM, Holtzman, DM.Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature. 2009 Oct 15;461(7266):91622.Google Scholar
229Price, JL, McKeel, DW Jr., Buckles, VD, et al.Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009 Jul;30(7):102636.Google Scholar
230Mondadori, CR, Buchmann, A, Mustovic, H, et al.Enhanced brain activity may precede the diagnosis of Alzheimer’s disease by 30 years. Brain. 2006 Nov;129(Pt 11):290822.Google Scholar
231Knight, WD, Kim, LG, Douiri, A, Frost, C, Rossor, MN, Fox, NC.Acceleration of cortical thinning in familial Alzheimer’s disease. Neurobiol Aging. 2011 Oct;32(10):176573.Google Scholar
232Ridha, BH, Barnes, J, Bartlett, JW, et al.Tracking atrophy progression in familial Alzheimer’s disease: a serial MRI study. Lancet Neurol. 2006 Oct;5(10):82834.Google Scholar
233Gomez-Isla, T, Price, JL, McKeel, DW Jr., Morris, JC, Growdon, JH, Hyman, BT.Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci. 1996 Jul 15; 16(14):4491500.Google Scholar
234West, MJ, Kawas, CH, Stewart, WF, Rudow, GL, Troncoso, JC.Hippocampal neurons in pre-clinical Alzheimer’s disease. Neurobiol Aging. 2004 Oct;25(9):120512.Google Scholar
235Jack, CR Jr., Albert, MS, Knopman, DS, et al.Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 May;7(3): 25762.Google Scholar
236Jack, CR Jr., Knopman, DS, Jagust, WJ, et al.Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010 Jan;9(1):11928.Google Scholar
237Jack, CR Jr., Lowe, VJ, Weigand, SD, et al.Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain. 2009 May0;132(Pt 5):135565.Google Scholar
238Heister, D, Brewer, JB, Magda, S, Blennow, K, McEvoy, LK.Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology. 2011 Oct 25;77(17):161928.Google Scholar
239Kalback, W, Watson, MD, Kokjohn, TA, et al.APP transgenic mice Tg2576 accumulate Abeta peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer’s disease senile plaques. Biochemistry. 2002 Jan 22; 41(3):9228.CrossRefGoogle ScholarPubMed
240Shen, J, Bronson, RT, Chen, DF, Xia, W, Selkoe, DJ, Tonegawa, S.Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997 May 16;89(4):62939.Google Scholar
241Selkoe, D, Kopan, R.Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:56597.CrossRefGoogle ScholarPubMed
242Wong, GT, Manfra, D, Poulet, FM, et al.Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004 Mar 26;279(13):1287682.Google Scholar