The central hypothesis to be tested in the proposed studies is that key cellular abnormalities in Alzheimer's disease are expressed in and can usefully be studied at the cellular level in non-neural tissues as well as the brain. The studies focus on tissue culture models and specifically cultured skin fibroblasts. Project 1 will test the validity and utility of a culture system in which fibroblasts appear to express antigens normally associated with neurons in culture or in vivo (neuron-specific enolase [NSE] and neurofilaments [NF]), and in which a significantly higher proportion of fibroblasts from Alzheimer patients react with antibodies to paired helical filaments than do cells from controls. The molecules responsible for these reactions will be characterized. The relation of the accumulation of those molecules to biological age in culture and to mitochondrial and other metabolic abnormalities described in Alzheimer cells will be determined, and the clinical specificity and diagnostic utility of this observation tested. Project 2 will examine signal transduction mechanisms in homeostasis, the inositol phosphate cascade, and cyclic AMP). The emphasis will be on elucidating basic mechanisms including relationships to biological age and to mechanisms studied in Project 1. Project 5 will compare mitochondrial metabolism in Alzheimer and control cells, determining the mechanisms underlying the reported mitochondrial abnormalities and particularly the fragility in Alzheimer and control cells, following up on reports of abnormal DNA repair. Project 7 will define the mechanisms underlying the loss of neuropeptide plasticity in aging superior cervical neurons in culture; it relates to the other studies, since age-is a major risk factor Alzheimer's disease. A clinical Pilot Project will examine writing abnormalities in Alzheimer patients. The cores will provide support activities, including the provision for all studies of fibroblasts of cells grown under meticulously controlled conditions, with Alzheimer and control cells matched for biological age in culture as well as chronological age and gender of donor.
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