The amyloid deposits in senile plaques of Alzheimer's disease brain are derived from a family of polypeptides termed Alzheimer's amyloid precursor proteins (beta-APP). In addition to the excessive deposition of amyloid proteins, Alzheimer's disease is characterized by a variety of neurochemical deficits including decreases in forebrain cholinergic, noradrenergic and serotonergic markers. These neurotransmitter deficits are accompanied by the loss of the cortically projecting cholinergic cells of the nucleus basalis of Meynert (nbM) noradrenergic cells of the locus coeruleus, and serotonergic cells of the raphe nuclei. Lesions of these transmitter systems lead to significant impairment of cognitive function. We have found that lesions of the nbM in the rat lead to a greater than 2.5 fold increase in the synthesis of, and mRNA for, the 695 form of the Alzheimer's amyloid precursor protein. The induction is rapid (within 1 hour of lesioning), and persists for at least 45 days post lesion. This induction exhibits specificity to beta-APP in that neither overall protein synthesis nor GFAP synthesis are altered by the lesion. We have observed similar increases in beta-APP synthesis following lesions of the forebrain noradrenergic and serotonergic systems. In addition, preliminary results suggest that modulation of beta-APP synthesis is specific to decreased presynaptic neurotransmitter activity since augmentation of cholinergic activity by chronic (2 weeks) physostigmine administration, or some other perturbations of the CNS fail to affect cortical beta-APP synthesis. These results demonstrate that the synthesis of beta-APP can be modulated and studied by specific manipulations of the CNS in animal model systems which mimic many of the neurochemical changes in AD. The study of neurotransmitter modulation of beta-APP synthesis in vivo may shed light on the mechanisms involved in the accumulation of amyloid proteins and senile plaque biogenesis in Alzheimer's disease. The studies proposed in this application aim to describe the cellular and molecular mechanisms responsible for neurotransmitter modulation of beta- APP synthesis in vivo. We hypothesize that increased beta-APP synthesis may be a natural response to neurotransmitter deficits and may be involved in neurotrophism. We propose different studies to describe (a) whether the beta-APP induction is temporary (due to degenerative process) or permanent (due to the absence of innervation) (Specific Aim 1); (b) whether mature beta-APP ever accumulates (Specific Aim 1); (c) whether the beta-APP response to these lesions is generalized over all regions of the cortex, or whether it occurs in specific cell groups of specific cortical laminae and regions (Specific Aims 2 and 4); (d) whether the beta-APP induction response is differentially regulated in young vs aged rats, and cognitively impaired vs cognitively intact aged rats (Specific Aim 3); (e) whether multiple lesions will result in an elevated induction of cortical beta-APP and lead to other secondary AD-like neuropathologies (Specific Aim 4). In addition, these studies will establish the conditions for maximal induction of beta-APP.
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