The goal of this project is to use biochemical, molecular and cellular means to elucidate the mechanisms thatlead to brain aging and cognitive decline.
The specific aims of Project 2 are to: 1) Determine age-relatedchanges in gene expression in prefrontal cortical white and gray matter, and in electrophysiologicallycharacterized pyramidal neurons. Using gene microarray analyses, we will assess whether changes in geneexpression in prefrontal subcortical white matter precede cognitive impairment and whether the expressionof genes specifically implicated in aging and cognitive function, such as Klotho, are altered in cognitivelyimpaired, aged animals, 2) Determine the function of Klotho in brain and neuronal cultures. The anti aginggene Klotho is of particular interest because a deletion of the gene has been shown to cause prematureaging in mice with manifestations resembling aging in humans. We found a decrease in its expression in thewhite matter of aged monkeys in our microarray analysis. We plan to test the hypothesis that the age-relateddecreased expression of Klotho causes oligodendrocyte injury and demyelination, and neuronal dysfunction,and 3) Decipher the mechanism of CNP accumulation, and determine the role of the proteasome andcalpain-1 in CNP degradation. Our earlier studies in brain white matter showed an increased expression andfragmentation of CNP, an oligodendrocyte microtubule-associated protein that participates in the regulationof myelin proteins and membrane formation. It is hypothesized that these CNP changes are related to anage associated decrease in proteasomal degradation and posttranslational modifications of CNP in the lipidrafts of the oligodendrocytes that leads to oligodendrocyte and myelin dysfunction. The proposed studies willuse an array of molecular and biochemical studies designed to test the specific hypothesis that normal age-related cognitive decline begins in middle age with white matter degeneration and inflammation leading toneuronal dysfunction, and may suggest points for therapeutic intervention in the aging process.
Showing the most recent 10 out of 151 publications
