The Role of Neurofilaments in Alzheimer's Disease

There is a normal decline in neurofilament mRNA expression during aging which is more pronounced in Alzheimer’s disease. It is also known that there is an inverse relationship between the number of neurofilaments and paired helical filaments (PHF), a hallmark of the disease. In this application, we proposed to test the hypothesis that changes in levels of neurofilament proteins can contribute to some of the pathological changes associated with Alzheimer’s disease. To address this problem, we recently generated mice whose neurofilament genes have been inactivated. Our preliminary analysis of mice with altered levels of neurofilament proteins revealed dramatic cellular changes of relevance to the problem of Alzheimer’s disease including hypotrophy of axons, alteration of intracellular transport, up-regulation of tubulin and evidence of hyperhosphorylation of tau, the major component of PHF in Alzheimer’s disease. The specific aims of this proposal are: 1) To further study the changes in the levels and phosphorylation of tau in mice having altered ratios of neurofilament proteins. 2) To examine if a redistribution of tau in dendrites and formation of paired helical filaments (PHF) occur during aging in these mice. 3) To examine in neurofilament-deficient mice the changes in levels and processing of the amyloid precursor protein (APP) and beta-amyloid since a characteristic pathological change in the brain of Alzheimer’s disease patients is the deposition of abnormal aggregates of beta-amyloid. The long term goals of this research are to better understand some of the molecular mechanisms associated with Alzheimer’s pathology and to derive a pertinent mouse model of the disease.