Cognitive decline and synaptic change in the aging marmoset

项目总结/文摘

PROJECT SUMMARY/ABSTRACT An unfortunate consequence of increased human lifespan is that aging-related neurodegenerative diseases such as Alzheimer’s disease (AD) are a growing burden. The single greatest risk factor for cognitive decline and AD is aging, yet we lack an understanding of how aging predisposes the brain to these consequences. Synaptic alterations that correlate with cognitive dysfunction are prevalent in both normal and pathological aging, though they are distinct from one another. In normal aging, subtle synaptic changes that affect the number of functional glutamatergic receptors lead to a decrease in synaptic efficacy and result in cognitive decline. In AD, synaptic loss precedes cell death and is the neuropathological feature of AD that correlates most strongly with cognitive dysfunction. Synaptic changes are unmistakably an important feature of normal aging and pathological neurodegeneration, and the clear links to cognitive decline underscore the importance of simultaneously investigating these features of aging. Non-human primates (NHPs) have similar neuroanatomy, neurophysiology, and cognitive abilities to humans, and also can develop the hallmark neuropathologies of AD; Tau tangles and β-amyloid plaques. The proposed research develops the common marmoset (Callithrix jacchus) as a NHP model for simultaneously investigating aging-related cognitive decline and synaptic alterations. Compared to macaque monkeys with long lifespans (25-40 years), marmosets have a relatively short average lifespan of 9-10 years, enabling their use in longitudinal studies of aging. In Aim 1, aging-related deficits in marmosets’ performance of a hippocampus-dependent memory task, the Delayed Recognition Span Task (DRST), will be determined. Performance of this task declines with normal aging in humans and macaques and patients with mild AD are further impaired on the DRST compared to healthy elderly controls. This task has been developed for marmosets using an automated touch screen system within the animal’s home cage. This Aim will test the hypothesis that aged animals exhibit impaired memory capacity on the task, reflecting aging-related cognitive decline. In Aim 2, non-invasive positron emission tomography (PET) imaging will be used to measure synaptic alterations in the hippocampus of the marmosets used for cognitive testing in Aim 1. To do this, a PET tracer that selectively binds to AMPA receptors will be used. This Aim will test the hypothesis that aged marmosets have decreased tracer uptake in the hippocampus, reflecting decreased AMPA receptor density, compared to younger animals. Further, there will be a strong, positive correlation between AMPA receptor density and cognitive performance, measured via the DRST in Aim 1. Establishing this experimental platform for the simultaneous tracking of aging-related changes in both hippocampal-dependent memory and AMPA receptor density will enable future longitudinal investigations to elucidate the time course of synaptic changes and cognitive decline in the brains of marmosets. This could lead to novel ways to predict onset of neurodegeneration before clinical symptoms arise.