Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:44

Article

Rosen, Rebecca F.^1,8  Tomidokoro, Yasushi^2,10  Farberg, Aaron S.^1,9  Dooyema, Jeromy¹  Ciliax, Brian³  Preuss, Todd M.^1,4  Neubert, Thomas A.⁵  Ghiso, Jorge A.^2,6  LeVine, Harry, III⁷  Walker, Lary C.^1,3 

[1] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA

[2] NYU, Sch Med, Dept Pathol, New York, NY USA

[3] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[4] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA

[5] NYU, Sch Med, Dept Biochem & Mol Pharmacol, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY USA

[6] NYU, Sch Med, Dept Psychiat, New York, NY USA

[7] Univ Kentucky, Struct Biol Ctr, Dept Mol & Cellular Biochem, Ctr Aging, Lexington, KY USA

[8] NYU, Ctr Urban Sci & Progress, Brooklyn, NY 11201 USA

[9] Natl Soc Cutaneous Med, New York, NY USA

[10] Univ Tsukuba, Dept Neurol, Tsukuba, Ibaraki 3058577, Japan

关键词: Amyloid;    Cerebral amyloid angiopathy;    Primate;    Prion;    Seeding;    Tauopathy;    Senile plaques;   

DOI  :  10.1016/j.neurobiolaging.2016.04.019

来源: Elsevier

【 摘 要 】

The misfolding and accumulation of the protein fragment beta-amyloid (A beta) is an early and essential event in the pathogenesis of Alzheimer's disease (AD). Despite close biological similarities among primates, humans appear to be uniquely susceptible to the profound neurodegeneration and dementia that characterize AD, even though nonhuman primates deposit copious A beta in senile plaques and cerebral amyloid-beta angiopathy as they grow old. Because the amino acid sequence of A beta is identical in all primates studied to date, we asked whether differences in the properties of aggregated A beta might underlie the vulnerability of humans and the resistance of other primates to AD. In a comparison of aged squirrel monkeys (Saimiri sciureus) and humans with AD, immunochemical and mass spectrometric analyses indicate that the populations of A beta fragments are largely similar in the 2 species. In addition, A beta-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of A beta in a transgenic mouse model. However, the epitope exposure of aggregated A beta differs in sodium dodecyl sulfate-stable oligomeric A beta from the 2 species. In addition, the high-affinity binding of H-3 Pittsburgh Compound B to A beta is significantly diminished in tissue extracts from squirrel monkeys compared with AD patients. These findings support the hypothesis that differences in the pathobiology of aggregated A beta among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors. (C) 2016 Elsevier Inc. All rights reserved.

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