Alzheimers sjukdom (AD) är den vanligaste orsaken till demens och utgör 60% av alla demensfall. Tidiga symptom t.ex. försämrat närminne och svå-righet att uttrycka sig kommer smygande. Sjukdomen fortskrider sedan ofta ganska långsamt under flera år med en tilltagande försämring av minnes-funktion, språklig förmåga, orienterings förmåga, sviktande praktiska fär-digheter och personlighetsförändringar. Mot slutet av sjukdomen blir de drabbade individer ofta helt beroende av vård men dör oftast av andra orsa-ker t.ex. sekundära infektioner såsom lunginflammation. Normalt pågår sjukdomsförloppet under 7-10 år efter diagnos. Det finns inget botemedel mot Alzheimers sjukdom utan enbart lindrande behandling med mycket be-gränsad effekt vid sena stadier av sjukdom. Diagnosen för Alzheimers sjuk-dom baseras på sjuksjuk-domshistoria tillsammans med ett antal tester som utvär-derar minne, språk och spatial förmåga. Utöver detta används olika hjärnav-bildande metoder för att stödja diagnosen Alzheimers sjukdom och för att utesluta andra orsaker som t.ex. stroke eller andra demenssjukdomar. En definitiv diagnos av Alzheimers sjukdom baseras på hjärnobduktion och påvisande av amyloida plack och neurofibrillära nystan (Figure 1). Patolo-gens bedömning baseras på frekvens, anatomisk lokalisation och patientens ålder.
Amyloida plack består av fibriller av proteinet amyloid-beta (Aβ) och neuro-fibrillära nystan består av fibriller av proteinet tau, som är viktig för upp-byggnaden av cellskelettet. Länge var uppfattningen att amyloida plack var giftiga för nervcellerna men flera studier har visat att det är lösliga förstadier till fibrillärt Aβ, dvs. ansamling av oligomerer och protofibriller som troligen är närmare kopplat till nervcellsdöd. Flera behandlingsstrategier mot Alz-heimers sjukdom bygger på att hjälpa kroppen att göra sig av med Aβ-peptiden genom att administrera laboratorie-framställda antikroppar mot Aβ för att därigenom aktivera immunsystemet så att Aβ bryts ned. I avhandling-ens första arbete (Paper I), behandlades en AD-djurmodell med en kropp som selektivt binder protofibriller. Resultaten visade att denna anti-kropp förhindrade amyloid bildning vid tidig behandling genom att ta bort protofibriller och att dessa var nödvändiga förstadier till fibrillbildning vid Alzheimers sjukdom. Resultaten har lett till att Bioarctic Neuroscience/Eisai har vidareutvecklat en mänsklig variant av antikroppen, BAN2401, vilket testas på patienter i stora kliniska studier. Behandling mot protofibriller hade 52
ingen positiv inverkan på inlärning eller minne hos Alzheimermöss, vilket kan bero på val av minne- och inlärningstest. Det finns ett ökat behov av reproducerbara tester av högre kognitiv funktion för djurmodeller av mänsk-lig sjukdom. I avhandlingens andra arbete (Paper II) undersöktes bland annat minne och inlärning i ett nytt automatiserat beteendetest. Alzheimer-mössen uppvisade nedsatt minne- och inlärningsförmåga, hyperaktivitet, viktminskning och nedsatt kognitiv flexibilitet. Dessa beteendeavvikelser kan kopplas till nedsatt hippokampal funktion, ett område djupt inne i hjär-nan, som påverkas tidigt vid Alzheimers sjukdom.
Hur proteinerna Aβ och tau interagerar på molekylär nivå vid Alzheimers sjukdom är fortfarande okänt. Tau proteinet binder till och stabiliserar cells-kelettet som är viktig för struktur och transport inom nervcellen. Det har föreslagits att Aβ och tau tillsammans förhindrar transport av näringsämnen inom nervceller. Exon 10 är ett litet gen-segment av tau genen som kodar för den region av tau som binder till cellskelettet. Tau’s förmåga att binda till cellskelettet bestäms bland annat huruvida exon 10 blir till protein. I avhand-lingen tredje arbete (Paper III), undersöktes den fysiologiska funktionen av exon 10 i en ny djurmodell. Avsaknad av exon 10 resulterade i nedsatt moto-rik hos djuren men förändrade inte minne- eller inlärnings-förmågan eller andra beteenden. Mössen uppvisade ingen inlagring av tau proteinet i vävna-den, vilket antyder på att processen av fibrillbildning initieras av andra icke-närvarande faktorer t.ex. tau- eller Aβ-aggregat. Tidigare studier med helt andra djurmodeller har visat att närvaro av Aβ kan ge ökad bildning av neurofibrillära nystan och att Aβ bryter ner cellskelettet genom sin effekt på tau. I avhandlingen fjärde arbete (Paper IV) undersöktes den molekylära interaktionen mellan Aβ och tau i en dubbel transgen djurmodell där Alz-heimermöss från Paper I-II korsades med tau-möss från Paper III. Studien visar att avsaknad av exon 10 leder till minskad plackbildning men ingen fibrillisering av tau proteinet. Avsaknad av fibrillärt tau kan bero skillnader i biokemiska processer i mänsklig hjärna och djurmodeller, exempelvis att de Aβ-aggregat som får tau att bilda fibriller inte bildas eller finns i för låga halter för att ha biologisk effekt i djurmodellerna. Det kan heller inte uteslu-tas att inlagring av Aβ och tau är två helt oberoende sjukdomsprocesser.
Sammanfattningsvis har avhandlingens arbete resulterat i en ny behandling strategi med antikropp mot Alzheimers sjukdom, utvärdering av nya beteen-detester av Alzheimermöss samt studier av kopplingen mellan Aβ och tau vid Alzheimers sjukdom med fokus på närvaro eller frånvaro av tau exon 10 vid proteinsyntesen.
53
Acknowledgements
This thesis work was performed at the Department of Public Health and Car-ing Sciences at the division of Molecular Geriatrics, at Rudbeck Laboratory, Uppsala University. This work has been supported by several funding agen-cies, which I am grateful for: Swedish Research Council (LL #2009-4567;
LN #2009-4389), The Swedish Brain Foundation, Alzheimer Foundation (LN, AG), Gamla Tjännarinnor Foundation, Demens foundation, Gun and Bertil Stohne Foundation (LN, AG), Magnus Bergvall Foundation, Åhléns Foundation, Lundströms Minne Foundation, Frimurar Foundation and Trolle-Wachmeisters Foundation (LN).
This journey has been plausible by the aid of several persons which I would like to thank;
Lars Nilsson, main supervisor, for being an outstanding source of never-ending knowledge and for being an excellent mentor through all these stud-ies! All of this work would have not been possible without your knowledge, ideas and practical help! Thanks for all the comments regarding this thesis and I have really missed you since you left for Norway!
Lars Lannfelt, co-supervisor, for giving me the opportunity to perform my doctoral studies in a stimulating scientific environment and for your support of my work.
Big thanks to all co-authors and collaborators for excellent papers! I would like to especially thank;
Anna Lord on Paper I for helping me getting started in the lab and for be-ing so friendly and kind!
Dag Sehlin, Hillevi Englund and Frida Ekholm-Petterson (Paper I) for all the work behind the antibody - mAb158!
Bengt Winblad, Abdul Mohammed and Alina Codita on Paper II for a good collaboration and for introducing me to the world of behavior and In-telliCage!
54
Pär Gellerfors and BioArctic Neuroscicence AB, for good collaborations and for the IntelliCage!
Dr. Nenad Bogdanovic for the histopathological pictures used in this thesis.
Mimmi Hedlund, Anne-Marie Ljungberg, Kristina Magnusson, Lena Skoglund and Micaela Vrede, for all the help in the Tau-project and for being so kind and friendly!
To all present and past members of MOLGER for great and entertaining coffee brakes, kick-offs, social events and for making it fun to go to work. It would take more than a couple of pages to proper acknowledge every one of you, so simply many thanks to (in disorganized order): Therese, Sofia, Ve-ronica, Joakim, Dag, Vilmantas, Thomas, Ola, Paul, Anna L, Hillevi, Frida, Lars N, Lars L, Martin, Kristina, Hedvig, Charlotte N, Charlotte S, Xiao, Lena, Stina, Linda, Anna E, Elisabeth I, Mimmi, Anne-Marie, Tsong, Elisabeth N, Leire, Gabriel and many others!
I would like to especially acknowledge two amazing friends over the years, Therese Fagerqvist and Sofia Söllvander! We have shared so much over the years (conferences, dinners, bachelorette-parties, wedding-details, preg-nancies etc.) and we have had a lot of fun! I hope that we continue to have more good times!
Till alla underbara vänner (ni vet vilka ni är) tack för alla middagar, träf-far, promenader och mamma-fika under åren!
Till min stora och växande familj:
Mamma Hilda och pappa Guillermo tack för ett stort stöd under dessa år, er kärlek och för ni lärt mig att allt är möjligt! Lill-brosan José, för din en-tusiasm och intresse i vad syrran gör och för att du är världen bästa bror!
Nikkhah-klanen & familjen Törnqvist-Nikka: som blivit viktiga personer i mitt liv! Tack för all underbara tider vi har haft under åren och för ert stöd!
Heman mitt största stöd i livet! Tack för att du är den du är och för att du alltid får mig att skratta. Till min underbara dotter Elena, som har lärt mig vad som är viktigast i livet! Älskar er oändligt mycket!
55
References
1. World Alzheimer Report - Long-term Care. 2013.
2. Wimo, A., B. Winblad, and L. Jonsson, The worldwide societal costs of dementia: Estimates for 2009. Alzheimers Dement, 2010. 6(2): p.
98-103.
3. World Alzheimer Report - Prevalence and Overview. 2009.
4. Alzheimer, A., Über eine eigenartige erkrankung der hirnrinde. All Z Psychiat, 1907. 64: p. 146-8.
5. Sipe, J.D., et al., Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the
International Society of Amyloidosis. Amyloid, 2012. 19(4): p. 167-6. 70. Zhu, C.W. and M. Sano, Economic considerations in the
management of Alzheimer's disease. Clin Interv Aging, 2006. 1(2):
p. 143-54.
7. Castellani, R.J., R.K. Rolston, and M.A. Smith, Alzheimer disease.
Dis Mon, 2010. 56(9): p. 484-546.
8. Schoonenboom, N.S., et al., Amyloid beta(1-42) and phosphorylated tau in CSF as markers for early-onset Alzheimer disease.
Neurology, 2004. 62(9): p. 1580-4.
9. Andreasen, N., et al., Cerebrospinal fluid levels of total-tau, phospho-tau and A beta 42 predicts development of Alzheimer's disease in patients with mild cognitive impairment. Acta Neurol Scand Suppl, 2003. 179: p. 47-51.
10. Reisberg, B., et al., Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med, 2003. 348(14): p. 1333-41.
11. Wenk, G.L., Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry, 2003. 64 Suppl 9: p. 7-10.
12. Glenner, G.G. and C.W. Wong, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun, 1984. 120(3): p.
885-90.
13. Masters, C.L., et al., Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A, 1985.
82(12): p. 4245-9.
14. Jarrett, J.T., E.P. Berger, and P.T. Lansbury, Jr., The carboxy terminus of the beta amyloid protein is critical for the seeding of 56
amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry, 1993. 32(18): p. 4693-7.
15. Mann, D.M., P.O. Yates, and B. Marcyniuk, Pathologic
heterogeneity of Alzheimer's disease. Arch Gen Psychiatry, 1988.
45(10): p. 962-3.
16. Selkoe, D.J., Alzheimer's disease: genes, proteins, and therapy.
Physiol Rev, 2001. 81(2): p. 741-66.
17. Lord, A., et al., Observations in APP Bitransgenic Mice Suggest that Diffuse and Compact Plaques Form via Independent Processes in Alzheimer's Disease. The American Journal of Pathology, 2011.
178(5): p. 2286-2298.
18. Suzuki, N., et al., High tissue content of soluble beta 1-40 is linked to cerebral amyloid angiopathy. Am J Pathol, 1994. 145(2): p. 452-19. 60. Kidd, M., Paired helical filaments in electron microscopy of
Alzheimer's disease. Nature, 1963. 197: p. 192-3.
20. Ballatore, C., V.M. Lee, and J.Q. Trojanowski, Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci, 2007. 8(9): p. 663-72.
21. St George-Hyslop, P.H., Molecular genetics of Alzheimer's disease.
Biol Psychiatry, 2000. 47(3): p. 183-99.
22. Reitz, C. and R. Mayeux, Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol, 2014.
23. Tanzi, R.E., et al., Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science, 1987. 235(4791): p. 880-4.
24. Kang, J., et al., The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature, 1987. 325(6106):
p. 733-6.
25. Goldgaber, D., et al., Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science, 1987. 235(4791): p. 877-80.
26. Goate, A., et al., Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature, 1991. 349(6311): p. 704-6.
27. Mullan, M., et al., A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet, 1992. 1(5): p. 345-7.
28. Citron, M., et al., Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production.
Nature, 1992. 360(6405): p. 672-4.
29. Walsh, D.M. and D.B. Teplow, Alzheimer's disease and the amyloid beta-protein. Prog Mol Biol Transl Sci, 2012. 107: p. 101-24.
57
30. Nilsberth, C., et al., The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci, 2001. 4(9): p. 887-93.
31. Jonsson, T., et al., A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature, 2012. 488(7409):
p. 96-9.
32. Olson, M.I. and C.M. Shaw, Presenile dementia and Alzheimer's disease in mongolism. Brain, 1969. 92(1): p. 147-56.
33. Mann, D.M., P.O. Yates, and B. Marcyniuk, Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age related continuum of pathological changes. Neuropathol Appl Neurobiol, 1984. 10(3): p. 185-207.
34. Wisniewski, K.E., et al., Alzheimer's disease in Down's syndrome:
clinicopathologic studies. Neurology, 1985. 35(7): p. 957-61.
35. Rovelet-Lecrux, A., et al., APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet, 2006. 38(1): p. 24-6.
36. Sherrington, R., et al., Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature, 1995. 375(6534):
p. 754-60.
37. Levy-Lahad, E., et al., Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science, 1995. 269(5226): p.
973-7.
38. Rogaev, E.I., 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): p. 775-8.
39. 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(2): p. 136-40.
40. Steiner, H., R. Fluhrer, and C. Haass, Intramembrane proteolysis by gamma-secretase. J Biol Chem, 2008. 283(44): p. 29627-31.
41. Strittmatter, W.J., et al., Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A, 1993. 90(5):
p. 1977-81.
42. Corder, E.H., et al., Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet, 1994. 7(2): p.
180-4.
43. Bales, K.R., et al., Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J Neurosci, 2009.
29(21): p. 6771-9.
44. Sharman, M.J., et al., APOE genotype results in differential effects on the peripheral clearance of amyloid-beta42 in APOE knock-in and knock-out mice. J Alzheimers Dis, 2010. 21(2): p. 403-9.
58
45. Bettens, K., K. Sleegers, and C. Van Broeckhoven, Genetic insights in Alzheimer's disease. Lancet Neurol, 2013. 12(1): p. 92-104.
46. Guerreiro, R., et al., TREM2 variants in Alzheimer's disease. N Engl J Med, 2013. 368(2): p. 117-27.
47. Cruchaga, C., et al., Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature, 2014. 505(7484): p.
550-4.
48. Hardy, J.A. and G.A. Higgins, Alzheimer's disease: the amyloid cascade hypothesis. Science, 1992. 256(5054): p. 184-5.
49. Parvathy, S., et al., Correlation between Abetax-40-, Abetax-42-, and Abetax-43-containing amyloid plaques and cognitive decline.
Arch Neurol, 2001. 58(12): p. 2025-32.
50. Arriagada, P.V., et al., Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology, 1992. 42(3 Pt 1): p. 631-9.
51. Terry, R.D., et al., Physical basis of cognitive alterations in
Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol, 1991. 30(4): p. 572-80.
52. Lue, L.F., et al., Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol, 1999. 155(3): p. 853-62.
53. Näslund, J., et al., Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. Jama, 2000.
283(12): p. 1571-7.
54. Wang, J., et al., The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging.
Exp Neurol, 1999. 158(2): p. 328-37.
55. McLean, C.A., et al., Soluble pool of Abeta amyloid as a
determinant of severity of neurodegeneration in Alzheimer's disease.
Ann Neurol, 1999. 46(6): p. 860-6.
56. Holcomb, L.A., et al., Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet, 1999. 29(3): p. 177-85.
57. Hsia, A.Y., et al., Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci U S A, 1999. 96(6): p. 3228-33.
58. Mucke, L., et al., High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice:
synaptotoxicity without plaque formation. J Neurosci, 2000. 20(11):
p. 4050-8.
59. Hutton, M., et al., Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature, 1998. 393(6686): p. 702-5.
59
60. Spillantini, M.G., et al., Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A, 1998. 95(13): p. 7737-41.
61. Lewis, J., et al., Neurofibrillary tangles, amyotrophy and
progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet, 2000. 25(4): p. 402-5.
62. Allen, B., et al., Abundant tau filaments and nonapoptotic
neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci, 2002. 22(21): p. 9340-51.
63. Tanemura, K., et al., Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci, 2002.
22(1): p. 133-41.
64. Santacruz, K., et al., Tau suppression in a neurodegenerative mouse model improves memory function. Science, 2005. 309(5733): p. 476-65. 81. Ramsden, M., et al., Age-dependent neurofibrillary tangle
formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci, 2005. 25(46): p. 10637-47.
66. Lewis, J., et al., Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science, 2001.
293(5534): p. 1487-91.
67. Luan, K., J.L. Rosales, and K.Y. Lee, Viewpoint: Crosstalks between neurofibrillary tangles and amyloid plaque formation.
Ageing Res Rev, 2013. 12(1): p. 174-81.
68. Kumar, S. and J. Walter, Phosphorylation of amyloid beta (Abeta) peptides - a trigger for formation of toxic aggregates in Alzheimer's disease. Aging (Albany NY), 2011. 3(8): p. 803-12.
69. Hardy, J. and D.J. Selkoe, The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.
Science, 2002. 297(5580): p. 353-6.
70. Rajendran, L. and W. Annaert, Membrane trafficking pathways in Alzheimer's disease. Traffic, 2012. 13(6): p. 759-70.
71. Golde, T.E., et al., Expression of beta amyloid protein precursor mRNAs: recognition of a novel alternatively spliced form and quantitation in Alzheimer's disease using PCR. Neuron, 1990. 4(2):
p. 253-67.
72. Wolfe, M.S. and S.Y. Guenette, APP at a glance. J Cell Sci, 2007.
120(Pt 18): p. 3157-61.
73. Ring, S., et al., The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J Neurosci, 2007. 27(29): p. 7817-26.
74. Haass, C., et al., Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature, 1992. 359(6393): p. 322-5.
60
75. Seubert, P., et al., Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature, 1992. 359(6393): p.
325-7.
76. Näslund, J., et al., Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging. Proc Natl Acad Sci U S A, 1994. 91(18): p. 8378-82.
77. Roher, A.E., et al., Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease. J Biol Chem, 1993. 268(5): p. 3072-78. 83. Ju, Y.E., B.P. Lucey, and D.M. Holtzman, Sleep and Alzheimer
disease pathology--a bidirectional relationship. Nat Rev Neurol, 2014. 10(2): p. 115-9.
79. Mikulca, J.A., et al., Potential novel targets for Alzheimer pharmacotherapy: II. Update on secretase inhibitors and related approaches. J Clin Pharm Ther, 2014. 39(1): p. 25-37.
80. Asai, M., et al., Putative function of ADAM9, ADAM10, and
ADAM17 as APP alpha-secretase. Biochem Biophys Res Commun, 2003. 301(1): p. 231-5.
81. Fahrenholz, F., et al., Alpha-secretase activity of the disintegrin metalloprotease ADAM 10. Influences of domain structure. Ann N Y Acad Sci, 2000. 920: p. 215-22.
82. Kuhn, P.H., et al., ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J, 2010. 29(17): p. 3020-32.
83. Vassar, R., et al., Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
Science, 1999. 286(5440): p. 735-41.
84. Kandalepas, P.C., et al., The Alzheimer's beta-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol, 2013. 126(3): p. 329-52.
85. De Strooper, B., Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron, 2003. 38(1):
p. 9-12.
86. Chasseigneaux, S. and B. Allinquant, Functions of Abeta, sAPPalpha and sAPPbeta : similarities and differences. J Neurochem, 2012. 120 Suppl 1: p. 99-108.
87. Iwata, N., et al., Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med, 2000. 6(2): p.
143-50.
88. Kurochkin, I.V. and S. Goto, Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett, 1994. 345(1): p. 33-7.
61
89. Kim, J., J.M. Basak, and D.M. Holtzman, The role of apolipoprotein E in Alzheimer's disease. Neuron, 2009. 63(3): p. 287-303.
90. Bendiske, J. and B.A. Bahr, Lysosomal activation is a compensatory response against protein accumulation and associated
synaptopathogenesis--an approach for slowing Alzheimer disease? J Neuropathol Exp Neurol, 2003. 62(5): p. 451-63.
91. Meyer-Luehmann, M., et al., Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science, 2006.
313(5794): p. 1781-4.
92. Jarrett, J.T. and P.T. Lansbury, Jr., Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell, 1993. 73(6): p. 1055-8.
93. Harper, J.D. and P.T. Lansbury, Jr., Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and
physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem, 1997. 66: p. 385-407.
94. Roher, A.E., et al., Morphology and toxicity of Abeta-(1-42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer's disease. J Biol Chem, 1996. 271(34): p. 20631-5.
95. Walsh, D.M., et al., Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
Nature, 2002. 416(6880): p. 535-9.
96. Kuo, Y.M., et al., Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem, 1996. 271(8): p.
4077-81.
97. Chromy, B.A., et al., Self-assembly of Abeta(1-42) into globular neurotoxins. Biochemistry, 2003. 42(44): p. 12749-60.
98. Klein, W.L., W.B. Stine, Jr., and D.B. Teplow, Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer's disease. Neurobiol Aging, 2004. 25(5): p. 569-80.
99. Lambert, M.P., et al., Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl
99. Lambert, M.P., et al., Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl