Amyloid Beta Oligomer Induction of Alzheimer's Disease in Nonhuman Primates

PROJECT SUMMARY Patients with Alzheimerandapos s diseaseADsuffer a progressive loss of memory and cognitive abilityand eventual loss of basic bodily functions and deathCurrentlyof Americans overhave AD and its incidence and toll on the healthcare system continues to rise with significant societal impactThere are no treatments for AD to prevent its inexorable courseand a principal obstacle to developing new therapies for AD has been the inadequacy of available preclinical modelingwhich almost exclusively involves rodentsAs nonhuman primatesNHPsshare greater homology to humans than rodents in all respectsincluding genomics and physiologycognitive processingneuronal network complexitywhite gray matter ratiosdynamics of drug target interactionsand the triggers of age associated pathophysiologythe long term goal of this project is to develop a new NHP model of AD that can be standardized and deployed in rigorousreproducible studies to overcome critical current deficiencies in translating preclinical studies into novel clinical diagnostic strategies and therapiesThe objective of this application is to expand and advance recent preliminary work on a new NHP model of AD involving intrathecal administration of amyloidoligomersA OsThe hypothesis is that A Os will trigger a cascade of accelerated pathology that mimics the changes occurring in the brains of AD patientsThis hypothesis is based on a growing consensus in the AD research fieldbacked by strong datathat 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 declineThe hypothesis will be tested in statistically meaningful designs by pursing the following two specific aimsDetermine the appropriate dose of A O and intervals of dosingandIdentify the persistence of induced biochemical and structural deficits and AD pathology following termination of A O infusionThese studies will utilize in lifeMRIand post mortem measurementsimmunohistochemistrybiochemistryto establish the impact of A Os administration in the brain of the StKitts green monkeya species that has been well characterized for its propensity to develop naturally occurring features of AD pathologyThe approach is innovative because it represents a substantial shift from current AD research paradigms and tests a novel theoretical conceptThe research is significant because it is expected to overcome critical deficiencies in current animal AD models by validating an acceleratedinducible NHP model of sporadic AD and permit effective translation of basic studies into novel clinical diagnostic strategies and therapiesSuccess with this model development program would provide a valuable resource to academicbiotechnologypharmaceutical and diagnostic laboratories in need of a reliable preclinical model of AD for basic researchand diagnostic and therapeutic development PROJECT NARRATIVE This project is relevant to public health because establishing a new model of Alzheimerandapos s disease similar to the human condition would increase understanding of its pathology and lead to earlier diagnoses and new and more effective treatmentsThe research has direct relevance to the goals of several NIH institutes including NIANIBIBNIEHSNIMHNINDS and NIAID and is relevant to the part of NIHandapos s mission that pertains to fostering fundamental discoveries and research strategies that will help to reduce the burdens of human disability