This project addresses the question of whether deficits in NGF- responsiveness may underly some of the neuropathological changes which occur in the basal forebrain in Alzheimer's disease (AD). We propose to test the hypothesis that expression of the nerve growth factor (NGF-R) gene is a sensitive indicator of the morphological integrity of basal forebrain cholinergic neurons (Ch1 - Ch4) cell groups), with increased levels of NGF-R mRNA and neuronal hypertrophy correlated with high levels of NGF in cortical target regions, and decrease levels of NGF-R and neuronal atrophy correlated with growth factor deprivation. In situ hybridization of NGF-R mRNA will be combined with quantitative measures of cell number and cellular hybridization intensity to document changes in NGF-R gene expression within components of the Ch1-Ch4 cell groups in AD. One mechanism by which amyloid deposition may occur with cortical target regions is by changes in the expression of the amyloid protein precursor (APP) gene within cortically-projecting cholinergic neurons of the basal forebrain. Thus, we will test the hypothesis that a specific form of APP mRNA transcript may be preferentially correlated with decreased NGF- responsiveness in Alzheimer's disease. These experiments will combine in situ hybridization methods with recently developed reverse transcriptase- polymerase chain reaction (R-PCR) to provide relative quantification of changes in the ratios of APP mRNA in AD.
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