This program is designed to determine the neurophysiological, biochemical, pathological and anatomical implications of the accumulation of D-aspartate with age in the protein of human brain white matter, a phenomenon recently discovered in this laboratory. The steady accumulation of D-aspartic acid, presumed to result from racemization of the common L-acid, may be related to diseases and dysfunctions of aging, as the accumulation of the unnatural D-form seems to imply little or no turnover of the myelin-rich white matter where it is found to occur. We will seek to relate D-aspartate accumulation rate with altered functions associated with specific brain regions, with such age- or myelin-related pathologies as senile dementia, Parkinson's, Alzheimer's and Binswanger's Diseases, and with chemical factors such as drug or alcohol abuse, calcium imbalance or the presence of heavy metals. D-aspartyl residue accummulation rates will be measured in different polypeptide species through isolation of purified myelin protein fractions, and the rate of accumulation will be related to protein carboxymethyl-transferase activity differences between normal and pathological brains. A cooperative arrangement between the Universities of Miami and California (Los Angeles and Irvine), will bring the skills of chemists, biochemists, neurophysiologists and pathologists to bear on the problem, with the ultimate goal of seeking intervention mechanisms for age-related brain pathology or dysfunction related to racemization.
