Recent 31P NMR studies from this laboratory have demonstrated increased levels of phosphomonoesters (PME) in Alzheimer disease (AD) brain as compared to normal and neurological controls and increased levels of phosphodiesters (PDE) in neurological controls compared to normal controls. PME are predominantly precursors of membrane phospholipids and PDE are the breakdown products. One tentative interpretation of the AD results is a metabolic block at the rate-limiting CTP:phosphoethamolamine (phosphocholine) cytidyltransferase enzyme (EC 18.104.22.168) in phospholipid synthesis. Preliminary HPLC studies of autopsy brain support this interpretation by demonstrating decreased levels of membrane phospholipids in AD brain. To pursue this possibility further qualitative and quantitative HPLC membrane phospholipid analyses of AD, Parkinson's disease (PD) and normal control brains are proposed. The phospholipid levels will be correlated with levels of PME and PDE and the numbers of senile plaques (SP) and neurofibrillary tangles (NFT) in AD, PD and control brain. These correlations will investigate the specificity of the findings for AD. Studies in the Fischer 344 rat to date have demonstrated remarkable effects of brain development and aging on high-energy phosphate and membrane phospholipid metabolism. The proposed studies will investigate the effects of graded anoxia or ischemia at 7 different ages (newborn-24months) on brain high-energy phosphate, membrane phospholipid and fatty acid metabolism. These studies could provide insights into the role of brain aging on its response to brief anoxia or ischemia.
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