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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Neurology C Study Section (NEUC)
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University of Rochester
Schools of Dentistry
United States
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Mah, V H; Eskin, T A; Kazee, A M et al. (1992) In situ hybridization of calcium/calmodulin dependent protein kinase II and tau mRNAs;species differences and relative preservation in Alzheimer's disease. Brain Res Mol Brain Res 12:85-94
Koh, S; Higgins, G A (1991) Differential regulation of the low-affinity nerve growth factor receptor during postnatal development of the rat brain. J Comp Neurol 313:494-508
Higgins, G A; Olschowka, J A (1991) Induction of interleukin-1 beta mRNA in adult rat brain. Brain Res Mol Brain Res 9:143-8
Higgins, G A; Oyler, G A; Neve, R L et al. (1990) Altered levels of amyloid protein precursor transcripts in the basal forebrain of behaviorally impaired aged rats. Proc Natl Acad Sci U S A 87:3032-6
Higgins, G A; Koh, S; Neve, R L et al. (1990) Trophic regulation of basal forebrain gene expression in aging and Alzheimer's disease. Prog Brain Res 86:239-55
Neve, R L; Rogers, J; Higgins, G A (1990) The Alzheimer amyloid precursor-related transcript lacking the beta/A4 sequence is specifically increased in Alzheimer's disease brain. Neuron 5:329-38
Higgins, G A; Mufson, E J (1989) NGF receptor gene expression is decreased in the nucleus basalis in Alzheimer's disease. Exp Neurol 106:222-36
Higgins, G A; Koh, S; Chen, K S et al. (1989) NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat. Neuron 3:247-56
Koh, S; Oyler, G A; Higgins, G A (1989) Localization of nerve growth factor receptor messenger RNA and protein in the adult rat brain. Exp Neurol 106:209-21