Amyloid beta peptide levels and its effects on hippocampal acetylcholine release in aged, cognitively-impaired and -unimpaired rats.
Excessive extracellular deposition of amyloid beta (Abeta) peptide in neuritic plaques and degeneration of forebrain cholinergic neurones, which innervate the hippocampus and the neocortex, are the invariant characteristic features of Alzheimer's disease (AD). Studies of the pathological changes that characterize AD, together with several other lines of evidence, indicate that Abeta accumulation in vivo may initiate and/or contribute to the process of neurodegeneration observed in the AD brain. However, the underlying mechanisms by which Abeta peptide influences/causes degeneration of the basal forebrain cholinergic neurones in AD brains remain obscure. We reported earlier that nM concentrations of Abeta-related peptides, under acute conditions, can potently inhibit K+-evoked endogenous acetylcholine (ACh) release from the hippocampus and the cortex but not from striatum in young adult rats (J. Neurosci. 16 (1996) 1034). In the present study, to determine whether the effects of Abeta peptides alter with normal aging and/or cognitive state, we have measured Abeta1-40 levels and the effects of exogenous Abeta1-40 on hippocampal ACh release in young adult as well as aged cognitively-unimpaired (AU) and -impaired (AI) rats. Endogenous levels of Abeta(1-40) in the hippocampus are significantly increased in aged rats. Additionally, 10 nM Abeta1-40 potently inhibited endogenous ACh release from the hippocampus of the three groups of rats, but the time-course of the effects clearly indicate that the cholinergic neurones of AI rats are more sensitive to Abeta peptides than either AU or young adult rats. These results, together with earlier reports, suggest that the processing of the precursor protein of Abeta peptide alters with normal aging and the response of the cholinergic neurones to the peptide possibly varies with the cognitive status of the animals.
Vaucher
E
E
Department of Psychiatry, Douglas Hospital Research Center, McGill University, Quebec, H4H 1R3, Montreal, Canada.
Aumont
N
N
Pearson
D
D
Rowe
W
W
Poirier
J
J
Kar
S
S
D000109:Acetylcholine / Q000378:metabolism*; D000375:Aging / Q000378:metabolism* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000378:metabolism* / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D000109:Acetylcholine