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 (cholineacetyltransferase; ChAT) activity losses correlate strongly with cognitive decline in AD. What precipitatesthese deficits, their time of onset, and first location during the progression of AD is currently unknown. Onepossible 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 usingPittsburgh Compound B (PiB; an amyloid-binding ligand) has identified prefrontal, posterior cingulate andprecuneus cortex as the first brain regions to accumulate AP plaques in vivo. Whether this early amyloidpathology is associated with regional changes in synapse number and ChAT activity levels during theprogression of AD is unknown. The present application will test several interrelated hypotheses, that in thesevulnerable brain areas (1) there is a reduction in synapse number and synaptic proteins as determined byunbiased ultrastructural stereology and western blotting, respectively; (2) ChAT activity is reduced(determined by quantitative biochemistry and immunohistochemistry), and (3) these morphologic andbiochemical changes correlate with regional Ap load (determined by quantitative ELISA and in vitro [H-3]PiBbinding) and with cognitive changes in NCI, MCI and mild AD. The exciting finding that in vitro [H-3]PiBbinding and in vivo PiB retention on PET scans correlate strongly (see Preliminary data) will enable us toconstruct 'virtual PiB scans' post-mortem, and correlate them with behavioral, cholinergic, and synapticstatus. Such data will enhance future clinical evaluations with PiB PET imaging. The significance of theseobservations in those NCI subjects displaying significant amounts of Ap pathology (possible'presymptomatic' AD), is of immense importance for determining the pathological interactions of Ap withcholinergic and synaptic alterations prior to first manifestations of clinical symptoms. The insight into how APaccumulation influences and relates to cholinergic/synaptic dysfunction, and how they all relate to clinicalsymptoms during disease progression, will facilitate development of stage-specific therapies for AD.
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