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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Review Article

淀粉样蛋白前体蛋白的羧基末端片段的神经元内积累是否会引发阿尔茨海默病的早期神经毒性？

卷 16, 期 5, 2019

页: [453 - 457] 页: 5

弟呕挨: 10.2174/1567205016666190325092841

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摘要

背景：阿尔茨海默病（AD）与最终在老年斑中接种的淀粉样蛋白β（Aβ）肽的细胞外积聚和聚集有关。最近的数据显示，它们的直接前体C99（βCTF）也在受AD影响的大脑以及AD样小鼠模型中积累。 C99始终比Aβ早得多，这表明该代谢物可能是AD病理学的早期原因。 C99主要在内溶酶体和自噬结构中积聚，其积累被描述为内源性和内溶血性病理性病理学的原因之一，其发生已被证实为AD的早期缺陷。 C99还伴有在相同细胞内细胞器内发生的C99衍生的C83（αCTF）积累。发现这两种CTF均二聚化，导致产生更高分子量的CTF，其通过聚集特异性抗体在原位进行免疫组织化学表征。 讨论：在这里，我们讨论研究证明C99和C99衍生的APP-CTF的积累与早期神经毒性之间的直接联系。我们讨论了C99在三重转基因小鼠以及新开发的AD动物模型中在内体 - 溶酶体病毒性功能障碍，神经炎症，早期脑网络改变和突触功能障碍以及记忆相关行为改变中的作用。 结论：本综述总结了目前的证据，表明β-分泌酶来源的APP C-末端片段C99在阿尔茨海默病的病因学中的潜在作用。

关键词: 阿尔茨海默病，C99，C83，C末端APP片段，二聚化，内溶酶体 - 自噬功能障碍，突触缺陷，脑网络改变，记忆相关行为，动物模型。

« Previous Next »
[1]
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256: 184-5. (1992).
[2]
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8: 595-608. (2016).
[3]
Checler F. Processing of the beta-amyloid precursor protein and its regulation in Alzheimer’s disease. J Neurochem 65: 1431-44. (1995).
[4]
Kimberly 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 100: 6382-7. (2003).
[5]
Kelleher RJ III, Shen J. Presenilin-1 mutations and Alzheimer’s disease. Proc Natl Acad Sci USA 114: 629-31. (2017).
[6]
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39: 409-21. (2003).
[7]
Lauritzen I, Pardossi-Piquard R, Bauer C, Brigham E, Abraham JD, Ranaldi S, et al. The beta-secretase-derived C-terminal fragment of betaAPP, C99, but not Abeta, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J Neurosci 32: 16243-5. (2012).
[8]
Kaur G, Pawlik M, Gandy SE, Ehrlich ME, Smiley JF, Levy E. Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein. Mol Psychiatry 22: 981-9. (2016).
[9]
Cavanagh C, Colby-Milley J, Bouvier D, et al. betaCTF-correlated burst of hippocampal TNFalpha occurs at a very early, pre-plaque stage in the TgCRND8 mouse model of Alzheimer’s disease. J Alzheimers Dis 36: 233-8. (2013).
[10]
Mondragon-Rodriguez S, Gu N, Manseau F, Williams S. Alzheimer’s transgenic model is characterized by very early brain network alterations and beta-ctf fragment accumulation: reversal by beta-secretase inhibition. Front Cell Neurosci 12: 121. (2018).
[11]
Nixon RA. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J 31: 2729-43. (2017).
[12]
Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 285: 13107-20. (2010).
[13]
Yang DS, Stavrides P, Saito M, Kumar A, Rodriguez-Navarro JA, Pawlik M, et al. Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. Brain 137: 3300-18. (2014).
[14]
Lauritzen I, Pardossi-Piquard R, Bourgeois A, Pagnotta S, Biferi MG, Barkats M, et al. Intraneuronal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-independent lysosomal-autophagic pathology. Acta Neuropathol 132: 257-76. (2016).
[15]
Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain 134: 258-77. (2010).
[16]
Orr ME, Oddo S. Autophagic/lysosomal dysfunction in Alzheimer’s disease. Alzheimers Res Ther 5: 53. (2013).
[17]
Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One 5: e9979. (2010).
[18]
Caccamo A, De Pinto V, Messina A, Branca C, Oddo S. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer’s disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature. J Neurosci 34: 7988-98. (2014).
[19]
Majumder S, Richardson A, Strong R, Oddo S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One 6: e25416. (2011).
[20]
Caccamo A, Ferreira E, Branca C, Oddo S. p62 improves AD-like pathology by increasing autophagy. Mol Psychiatry 22: 865-73. (2017).
[21]
Pasternak 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 6: 53-65. (2004).
[22]
Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD, Boyer-Boiteau A, et al. Alzheimer’s-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci USA 107: 1630-5. (2010).
[23]
Currais A, Fischer W, Maher P, Schubert D. Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain. FASEB J 31: 5-10. (2017).
[24]
Jager S, Leuchtenberger S, Martin A, Czirr E, Wesselowski J, Dieckmann M, et al. alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Abeta generation. J Neurochem 111: 1369-82. (2009).
[25]
Chen AC, Kim S, Shepardson N, Patel S, Hong S, Selkoe DJ. Physical and functional interaction between the alpha- and gamma-secretases: A new model of regulated intramembrane proteolysis. J Cell Biol 211: 1157-76. (2015).
[26]
Siegenthaler BM, Bali JB, Rajendran L. γ-secretase regulates the α- secreatse cleavage of the Alzheimer's disease, amyloid precursor protein, Sciencematters (2016) 10.19185/matters.201601000003.
[27]
Baranger K, Marchalant Y, Bonnet AE, Crouzin N, Carrete A, Paumier JM, et al. MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer’s disease. Cell Mol Life Sci 73: 217-36. (2015).
[28]
Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, et al. Beta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526: 443-7. (2015).
[29]
Kienlen-Campard P, Tasiaux B, Van Hees J, Li M, Huysseune S, Sato T, et al. Amyloidogenic processing but not amyloid precursor protein (APP) intracellular C-terminal domain production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs. J Biol Chem 283: 7733-44. (2008).
[30]
Winkler E, Julius A, Steiner H, Langosch D. Homodimerization protects the amyloid precursor protein c99 fragment from cleavage by gamma-secretase. Biochemistry 54: 6149-52. (2015).
[31]
Song Y, Hustedt EJ, Brandon S, Sanders CR. Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein. Biochemistry 52: 5051-64. (2013).
[32]
Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, et al. Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem 100: 23-35. (2007).
[33]
Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science 298: 789-91. (2002).
[34]
Nistico R, Pignatelli M, Piccinin S, Mercuri NB, Collingridge G. Targeting synaptic dysfunction in Alzheimer’s disease therapy. Mol Neurobiol 46: 572-87. (2012).
[35]
Tanzi RE. The synaptic Abeta hypothesis of Alzheimer disease. Nat Neurosci 8: 977-9. (2005).
[36]
Smith LM, Strittmatter SM. Binding sites for amyloid-beta oligomers and synaptic toxicity. Cold Spring Harb Perspect Med 7: 1-23. (2018).
[37]
Pardossi-Piquard R, Lauritzen I, Bauer C, Sacco G, Robert P, Checler F. Influence of genetic background on apathy-like behavior in triple transgenic AD mice. Curr Alzheimer Res 13: 942-9. (2016).
[38]
Bourgeois A, Lauritzen I, Lorivel T, Bauer C, Checler F, Pardossi-Piquard R. Intraneuronal accumulation of C99 contributes to synaptic alterations, apathy-like behavior, and spatial learning deficits in 3xTgAD and 2xTgAD mice. Neurobiol Aging 71: 21-31. (2018).
[39]
Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149: 708-21. (2012).
[40]
Goutagny R, Gu N, Cavanagh C, Jackson J, Chabot JG, Quirion R, et al. Alterations in hippocampal network oscillations and theta-gamma coupling arise before Abeta overproduction in a mouse model of Alzheimer’s disease. Eur J Neurosci 37: 1896-902. (2013).
[41]
Hebert SS, Horre K, Nicolai L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci USA 105: 6415-20. (2008).
[42]
Pera M, Alcolea D, Sanchez-Valle R, Guardia-Laguarta C, Colom-Cadena M, Badiola N, et al. Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease. Acta Neuropathol 125: 201-13. (2013).
[43]
Kim S, Sato Y, Mohan PS, Peterhoff C, Pensalfini A, Rigoglioso A, et al. Evidence that the rab5 effector APPL1 mediates APP-betaCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer’s disease. Mol Psychiatry 21: 707-16. (2016).
[44]
Saura CA, Chen G, Malkani S, Choi SY, Takahashi RH, Zhang D, et al. Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 25: 6755-64. (2005).
[45]
Mitani Y, Yarimizu J, Saita K, Uchino H, Akashiba H, Shitaka Y, et al. Differential effects between gamma-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci 32: 2037-50. (2005).
[46]
Tamayev R, D’Adamio L. Inhibition of gamma-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. Mol Neurodegener 7: 19. (2012).
[47]
Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369: 341-50. (2013).
[48]
Sambamurti K, Suram A, Venugopal C, Prakasam A, Zhou Y, Lahiri DK, et al. A partial failure of membrane protein turnover may cause Alzheimer’s disease: a new hypothesis. Curr Alzheimer Res 3: 81-90. (2006).
[49]
Dunys J, Valverde A, Checler F. Are N- and C-terminally truncated Abeta species key pathological triggers in Alzheimer’s disease? J Biol Chem 293: 15419-28. (2018).

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