Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease.
The misfolding and accumulation of the protein fragment β-amyloid (Aβ) 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 Aβ in senile plaques and cerebral amyloid-β angiopathy as they grow old. Because the amino acid sequence of Aβ is identical in all primates studied to date, we asked whether differences in the properties of aggregated Aβ 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 Aβ fragments are largely similar in the 2 species. In addition, Aβ-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of Aβ in a transgenic mouse model. However, the epitope exposure of aggregated Aβ differs in sodium dodecyl sulfate-stable oligomeric Aβ from the 2 species. In addition, the high-affinity binding of (3)H Pittsburgh Compound B to Aβ 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 Aβ among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors.
Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA. Electronic address: rebecca.rosen@nyu.edu.
Rebecca F
RF
Rosen
Department of Pathology, NYU School of Medicine, New York, NY, USA.
Yasushi
Y
Tomidokoro
Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
Aaron S
AS
Farberg
Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
Jeromy
J
Dooyema
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Brian
B
Ciliax
Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Todd M
TM
Preuss
Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine at the Skirball Institute, NYU School of Medicine, New York, NY, USA.
Thomas A
TA
Neubert
Department of Pathology, NYU School of Medicine, New York, NY, USA; Department of Psychiatry, NYU School of Medicine, New York, NY, USA.
Jorge A
JA
Ghiso
Department of Molecular & Cellular Biochemistry, Center on Aging, Center for Structural Biology, University of Kentucky, Lexington, KY, USA.
Harry
H
LeVine
Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: lary.walker@emory.edu.
Lary C
LC
Walker
D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006801:Humans; D008822:Mice, Transgenic; D012453:Saimiri; D024801:Tauopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology
D016229:Amyloid beta-Peptides
Amyloid; Cerebral amyloid angiopathy; Primate; Prion; Seeding; Senile plaques; Tauopathy