This is a request for the continuation of a multi-disciplinary program project to investigate the mechanisms of neurodegeneration and the emergence of inflammation in the aging brain. The project brings together investigators with a track record in the field, history of collaboration and complimentary expertise. The primary program investigators are Drs. Glabe, Lynch, Gall, Cotman, Tenner, LaFerla and Cummings. In the past grant period the primary focus was on the mechanisms causing the deposition of beta-amyloid and its consequences on neuronal and glial function and neurodegeneration. In the proposed continuation, Drs. Glabe and Lynch will evaluate the mechanisms of amyloid accumulation within neurons, examine possible lysosomal dysfunction in neuronal degeneration, and analyze regulatory mechanisms in the uptake of beta-amyloid and the propagation of its deposition. Drs. Gall, Cotman and Tenner will center their efforts on inflammation in the aging brain and the possible role of beta-amyloid and other inflammatory stimuli on the TNFalpha. Cotman will examine the induction of the pro-apoptotic TNF-Fas superfamily of receptors and ligands in the brain and the molecular mechanisms by which non- steroidal anti-inflammatory molecules regulate neurodegeneration. Tenner will study complement activation, particularly the contributions of C1q, and critically evaluate the hypothesis that beta-amyloid immunization can prevent build up of beta-amyloid in the absence of autoimmune responses. In this research and in the field in general, transgenic models offer many opportunities for testing hypothesis on the mechanisms driving age-related neurodegeneration. Dr. LaFerla will focus on the development and characterization of self transgenic animal models. An Administrative Core is proposed to coordinate efforts and a Tissue and Peptide Resources Core directed by Cummings with Co-PI LaFerla will postmortem brain tissues and peptides and assist in maintaining select transgenic animals.
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