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

The misfolding and accumulation of the protein fragment ß-amyloid (Aß) 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 Aß in senile plaques and cerebral amyloid-ß angiopathy as they grow old. Because the amino acid sequence of Aß is identical in all primates studied to date, we asked whether differences in the properties of aggregated Aß 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 Aß fragments are largely similar in the 2 species. In addition, Aß-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of Aß in a transgenic mouse model. However, the epitope exposure of aggregated Aß differs in sodium dodecyl sulfate-stable oligomeric Aß from the 2 species. In addition, the high-affinity binding of (3)H Pittsburgh Compound B to Aß 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 Aß among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors.