A major hallmark of Alzheimer's disease (AD) is the accumulation of neurotoxic p-amyloid (A(3) peptide in the brain. Inappropriate oligomerization of Ap peptides into soluble high molecular weight (HMW) species and the eventual deposition of A(3 peptides into extracellular A(3 plaques in the brain are major events involved in AD neuropathology and associated dementia. Accumulating evidence indicates a central role for soluble A|3 oligomers (with molecular weight higher than tetramers but lower than decamers) in preclinical AD cognitive deterioration as well as in AD dementia. The overall goal of the proposed studies in Project 3 is to identify bioactive grape seed extract (GSE)- polyphenolic compounds that can prevent AD-type amyloid neuropathology and cognitive deterioration in the Tg2576 mouse model of AD. The proposed studies are supported by preliminary evidence showing that a commercially available GSE (herein defined as NS-MA2 GSE) containing a variety of polyphenolic compounds, prevents the oligomerization of Ap peptides into soluble-extracellular HMW species and eventually AD - type Ap neuropathology, coincidental with the attenuation of spatial reference memory impairment in Tg2576 mice. Based on this consideration, the proposed studies are specifically designed to further identify and document how NS-MA2 GSE polyphenolic compounds are absorbed, metabolized and ultimately prevent AD-type cognitive deterioration in Tg2576 mice. The proposed studies will be the first to systematically identify GSE polyphenolic compounds in vivo using a combination of LC-tandem mass spectrorhetry and NMR techniques. Furthermore, this approach will make use of 14C labeled grape fractions and Accelerator Mass Spectrometry to accurately determine the pharmacokinetics of NS-MA2 GSE polyphenolic compounds in plasma and in the brain. Data from the proposed studies will provide impetus for immediate application to prevention of cognitive deterioration in AD, and potentially also in mild cognitive impairment (MCI), whose subjects are at high risk of developing AD dementia.
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