This project will focus on investigation of the molecular pathogenesis underlying mild cognitive impairment (MCI) prior to the onset of Alzheimer's disease (AD). Synapse and cholinergic enzyme (choline acetyltransferase;ChAT) activity losses correlate strongly with cognitive decline in AD. What precipitates these deficits, their time of onset, and first location during the progression of AD is currently unknown. One possible mechanism involves brain accumulation of soluble and insoluble forms of amyloid-beta peptide (A3), recently shown to impair synaptic function and correlate with cognitive decline. PET imaging using Pittsburgh Compound B (PiB;an amyloid-binding ligand) has identified prefrontal, posterior cingulate and precuneus cortex as the first brain regions to accumulate AP plaques in vivo. Whether this early amyloid pathology is associated with regional changes in synapse number and ChAT activity levels during the progression of AD is unknown. The present application will test several interrelated hypotheses, that in these vulnerable brain areas (1) there is a reduction in synapse number and synaptic proteins as determined by unbiased ultrastructural stereology and western blotting, respectively;(2) ChAT activity is reduced (determined by quantitative biochemistry and immunohistochemistry), and (3) these morphologic and biochemical changes correlate with regional Ap load (determined by quantitative ELISA and in vitro [H-3]PiB binding) and with cognitive changes in NCI, MCI and mild AD. The exciting finding that in vitro [H-3]PiB binding and in vivo PiB retention on PET scans correlate strongly (see Preliminary data) will enable us to construct """"""""virtual PiB scans"""""""" post-mortem, and correlate them with behavioral, cholinergic, and synaptic status. Such data will enhance future clinical evaluations with PiB PET imaging. The significance of these observations in those NCI subjects displaying significant amounts of Ap pathology (possible """"""""presymptomatic"""""""" AD), is of immense importance for determining the pathological interactions of Ap with cholinergic and synaptic alterations prior to first manifestations of clinical symptoms. The insight into how AP accumulation influences and relates to cholinergic/synaptic dysfunction, and how they all relate to clinical symptoms during disease progression, will facilitate development of stage-specific therapies for AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Rush University Medical Center
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