The hypothesis of this proposal is that a method can be developed to measure tau levels in the extracellular space of the brain (interstitial fluid–ISF) and that assessment of ISF tau in both normal mice as well as a variety of animal models that develop AD pathology will provide new insights into tau metabolism and the relationship between Aβ and tau in AD. If this method development is successful, it has a chance to tell us more about the pathophysiology of AD as well as a provide a novel way to screen for new AD treatments.
The goal of this project is to determine which types of cells and factors in the brain influence excess Abeta deposition in Alzheimer’s patients, using animal models of the disease.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by impairments in memory and cognition, neuronal loss and deposition of Abeta peptides that are derived from larger amyloid precursor proteins (APP). Rare, familial, early-onset autosomal dominant forms of Alzheimer’s disease (FAD) are caused by mutations in genes encoding APP, presenilin-1 (PS1) and presenilin-2 (PS2), polypeptides that are expressed ubiquitously in all central nervous system cell types and in peripheral organs. Transgenic animal (mouse) models for Alzheimer’s recapitulate the histological, synaptic and memory deficits that are classically associated with the human disorder. The goal of this project is to employ genetic and molecular strategies to test for the effects of FAD mutations in specific types of cells in the brains of Alzheimer’s animal models. The hypothesis is that deposition of Abeta in the brain can be influenced by various factors that are secreted not only by nerve cells, but other cells, e.g. glial cell in the neighborhood of the nerve cells. If they can identify which cell populations influence Abeta deposition, future studies will be aimed at identifying the exact factors that mediate Abeta deposition in animal models of Alzheimer’s disease. These factors then could guide novel drug discovery efforts to treat and prevent Alzheimer’s disease.
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