Amyloid Beta Oligomer Induction of Alzheimer's Disease in Nonhuman Primates - PROJECT SUMMARY
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 β-oligomers (AβOs). The hypothesis is that
AβOs 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 AβOs 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 AβO and intervals of dosing; and 2) Identify the persistence of induced biochemical and
structural deficits and AD pathology following termination of AβO infusion. These studies will utilize in-life (MRI)
and post-mortem measurements (immunohistochemistry, biochemistry) to establish the impact of AβOs
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.
