P2-067: PIB binding in Alzheimer's disease and nonhuman primate brain

Abstract

Background: The amyloid cascade hypothesis implicates the Abeta peptide as an upstream effector in Alzheimer’s disease (AD) neurodegeneration. However, the deposition of Abeta in the human brain is not always associated with frank dementia, inasmuch as abundant Abeta lesions are sometimes found in the brains of aged humans without overt cognitive impairment. Furthermore, age-related accumulation of cerebral Abeta is commonly observed in nonhuman primates, yet no nonhuman species has been shown to exhibit the full behavioral or pathological characteristics of AD. Because of their close biological relationship to humans, nonhuman primates are a unique model of nonpathologic Abeta accumulation. We have extensively characterized cerebral Abeta populations in AD, aged chimpanzees, rhesus macaques, and squirrel monkeys. Methods: Using immunohistochemistry, ELISA, immunoprecipitation/ MALDI-TOF MS and in vivo Abeta-seeding assays, we found that Abeta populations are quantitatively and qualitatively similar in AD and nonhuman primate brain. To explain the pathological differences between humans and other primates, we hypothesized that higher-order structural features distinguish toxic Abeta in AD brain from the relatively benign Abeta in nonhuman primates. Recent reports show that Pittsburgh Compound B (PIB), a radioligand used for in vivo PET imaging of amyloid, binds with high affinity and stoichiometry to AD brain but with low stoichiometry to synthetic Abeta and to the Abeta deposits in transgenic mouse brain. We measured the binding of 3H-PIB to cortical homogenates from AD and nonhuman primate cases, all of which had been characterized for total soluble and insoluble Abeta levels. Results: We found that 3H-PIB binds with low stoichiometry to Abeta in nonhuman primate cortical homogenates, even in cases with levels of Abeta equal to those in AD. Conclusions: These data suggest that cerebral beta-amyloid deposits in aged nonhuman primates, which naturally develop cerebral beta-amyloidosis over the course of many years, are structurally distinct from those in humans with AD, and that high-affinity PIB binding may be relatively selective for pathogenic Abeta in the AD brain.