The basal forebrain cholinergic neuronal (BFCN) system is intimately involved in the processes of learning, memory and attention. Within the human brain, the BFCN are selectively vulnerable in neurodegenerative diseases that afflict the elderly, such as Alzheimer's disease (AD). Recent preliminary observations from our laboratory indicate that the BFCN in AD display decreased expression of the gene for calmodulin kinase I (CaMKI) and increased immunoreactivity for the apoptotic protein Fas-associated death domain (FADD). It has been shown that CaMKI downregulation causes apoptosis in neurons. Thus, the downregulation of CaMKI expression in AD BFCN may be associated with apoptosis in these neurons. We have also observed that the BFCN display a substantial loss of the calcium binding protein calbindin-D28K (CB) in the course of normal aging in the human and a further decrease in Alzheimer's disease and that the BFCN which degenerate in Alzheimer's disease appear to be those which lose this protein in the course of normal aging. We hypothesize that downregulation of CaMKI in aging and AD BFCN results in upregulation of pro-apoptotic and / or downregulation of anti- apoptotic genes, and that changes in the expression of the above genes may be related to the age-related loss of CB, which is the earliest change observed in these neurons and may result in calcium dysregulation. The experiments in this proposal are intended to expand the scope of our previous studies using more novel methodologies. The proposed experiments will test the hypotheses that using single cell laser capture microscopy combined with quantitative real time PCR analysis : A. The BFCN in aging and Alzheimer's disease will display reduced expression of genes for CaMKI and the cyclic AMP response element binding protein (CREB), increased expression of pro-apoptotic genes and / or decreased expression of anti-apoptotic genes; B. altered expression of the above genes will occur primarily in CB-negative BFCN; C. decreased expression of CaMKI in cultured mouse BFCN using small inhibitory RNA will result in similar alterations in apoptosis- related genes; and D. increased expression of CB using adeno-associated viral vectors will result in upregulation of CaMKI. The results will have important implications for selective depletion of BFCN in aging and neurological diseases. They will also form the basis of more comprehensive future studies aimed at determining the causes and effects of the alterations of the above genes. ? ? ?
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