Certain hippocampal neuronal populations appear to be more vulnerable than other to the pathological consequences of Alzheimer's disease (AD). Neuropathological studies have shown that hippocampal neurons of the CA1 field, subiculum and entorhinal cortex are more prone to cell death, and the development of neurofibrillary tangles and neuritic (senile) plaques, than are neurons in the dentate gyrus and CA3 field. The major objective of this proposal is to use in situ hybridization in postmortem human brain tissue to study differences in gene expression between these cell populations, with particular regard to the expression of alternate transcripts of the amyloid-beta-protein gene, which may be differentially regulated during the course of AD. Preliminary studies suggest that total amyloid-beta-protein mRNA levels are elevated in the parasubiculum and entorhinal cortex in AD. We hypothesize that differential expression of amyloid-beta- protein mRNA plays a role in pathogenesis of AD, and thus these studies are designed to determine whether this AD-related increase in the parasubiculum is due to the expression of a particular form of amyloid-beta-protein mRNA, whose product may preferentially form amyloid deposits in the disease. Another hypothesis that will be tested is that cholinergic neurons in the medial septum and diagonal band complex contribute to hippocample gene products. Deficits in basal forebrain cholinergic function, including cell atrophy and loss, have been shown to occur early in AD, and may have pathological consequences for target neuronal populations in the hippocampal formation. Nerve growth factor, released from the hippocampus, appears to regulate the integrity of basal forebrain cholinergic neurons during the aging process, and the nerve growth factor receptor molecule provides a good marker for monitoring the integrity of the septo-hippocampal pathway examined using in situ hybridization and immunocytochemistry, in a rat model of human aging, the behaviorally-impaired aged rat. Subsequent studies will be undertaken in human brain, to determine if a similar relationship exists between nerve growth factor receptor regulation and hippocampal pathology and gene expression in AD.
