Patients with Alzheimer's disease (AD) suffer a progressive loss of memory and cognitive ability, and eventual loss of basic bodily functions and death. Currently 11% of Americans over 65 have AD and its incidence and toll on the healthcare system continues to rise with significant societal impact. There are no treatments for AD to prevent its inexorable course, and a principal obstacle to developing new therapies for AD has been the inadequacy of available preclinical modeling, which almost exclusively involves rodents. As nonhuman primates (NHPs) share greater homology to humans than rodents in all respects, including genomics and physiology, cognitive processing, neuronal network complexity, white/gray matter ratios, dynamics of drug/target interactions, and the triggers of age-associated pathophysiology, the long-term goal of this project is to develop a new NHP model of AD that can be standardized and deployed in rigorous, reproducible studies to overcome critical current deficiencies in translating preclinical studies into novel clinical diagnostic strategies and therapies. The objective of this application is to expand and advance recent preliminary work on a new NHP model of AD involving intrathecal administration of amyloid ?-oligomers (A?Os). The hypothesis is that A?Os will trigger a cascade of accelerated pathology that mimics the changes occurring in the brains of AD patients. This hypothesis is based on a growing consensus in the AD research field, backed by strong data, that A?Os are likely the toxic species that provoke deposition of the characteristic tangles and plaques in the brain together with loss of synapses and neurons and associated cognitive decline. The hypothesis will be tested in statistically meaningful designs by pursing the following two specific aims: 1) Determine the appropriate dose of A?O and intervals of dosing; and 2) Identify the persistence of induced biochemical and structural deficits and AD pathology following termination of A?O infusion. These studies will utilize in-life (MRI) and post-mortem measurements (immunohistochemistry, biochemistry) to establish the impact of A?Os administration in the brain of the St. Kitts green monkey, a species that has been well characterized for its propensity to develop naturally occurring features of AD pathology. The approach is innovative because it represents a substantial shift from current AD research paradigms and tests a novel theoretical concept. The research is significant because it is expected to overcome critical deficiencies in current animal AD models by validating an accelerated, inducible NHP model of sporadic AD and permit effective translation of basic studies into novel clinical diagnostic strategies and therapies. Success with this model development program would provide a valuable resource to academic, biotechnology, pharmaceutical and diagnostic laboratories in need of a reliable preclinical model of AD for basic research, and diagnostic and therapeutic development.
This project is relevant to public health because establishing a new model of Alzheimer's disease similar to the human condition would increase understanding of its pathology and lead to earlier diagnoses and new and more effective treatments. The research has direct relevance to the goals of several NIH institutes including NIA, NIBIB, NIEHS, NIMH, NINDS and NIAID and is relevant to the part of NIH's mission that pertains to fostering fundamental discoveries and research strategies that will help to reduce the burdens of human disability.
