PHARMACOLOGICAL MODULATION OF ALZHEIMERS BETA-AMYLOID PRECURSOR PROTEIN-LEVELS IN THE CSF OF RATS WITH FOREBRAIN CHOLINERGIC SYSTEM LESIONS

Abnormal deposition and accumulation of Alzheimer's amyloid beta-prote in (A beta) and degeneration of forebrain cholinergic neurons are amon g the principal features of Alzheimer's disease. Studies in rat model systems have shown that forebrain cholinergic deficits are accompanied by induction of cortical beta-amyloid precursor protein (beta-APP) mR NAs and increased levels of secreted beta-APP in the CSF. The studies reported here determined whether the CSF levels of secreted beta-APP c ould be altered pharmacologically. In different experiments, rats with lesions of the forebrain cholinergic system received injections of ve hicle, a muscarinic receptor antagonist scopolamine, or one of two cho linesterase inhibitors - diisopropyl phosphorofluoridate (DFP) or phen serine. Scopolamine was administered to determine whether the levels o f beta-APP in the CSF could be increased by anticholinergic agents. Th e cholinesterase inhibitors were administered to determine whether the forebrain cholinergic system lesion-induced increases in CSF beta-APP could be reduced by cholinergic augmentation. Scopolamine administrat ion led to a significant increase in the CSF levels of secreted beta-A PP in sham-lesioned rats. Phenserine, a novel, reversible acetyl-selec tive cholinesterase inhibitor, significantly decreased the levels of s ecreted beta-APP in the CSF of forebrain cholinergic system-lesioned r ats whereas DFP, a relatively non-specific cholinesterase inhibitor, f ailed to affect CSF levels of secreted beta-APP. These results suggest that the levels of secreted beta-APP in the CSF can be pharmacologica lly modulated but that this modulation is dependent upon the status of the forebrain cholinergic system and the pharmacological properties o f the drugs used to influence it.