Amyloid beta peptide levels and its effects on hippocampal acetylcholine release in aged, cognitively-impaired and -unimpaired rats

Excessive extracellular deposition of amyloid beta (A beta) peptide in neur itic plaques and degeneration of forebrain cholinergic neurones, which inne rvate the hippocampus and the neocortex. are the invariant characteristic f eatures of Alzheimer's disease (AD). Studies of the pathological changes th at characterize AD, together with several other lines of evidence, indicate that A beta accumulation in vivo may initiate and!or contribute to the pro cess of neurodegeneration observed in the AD brain. However, the underlying mechanisms by which A beta peptide influences/causes degeneration of the b asal forebrain cholinergic neurones in AD brains remain obscure. We reporte d earlier that nM concentrations of A beta -related peptides. under acute c onditions, can potently inhibit K+-evoked endogenous acetylcholine (ACh) re lease from the hippocampus and the cortex but not from striatum in young ad ult rats (J. Neurosci. 16 (1996) 1034). In the present study, to determine whether the effects of A beta peptides alter with normal aging and/or cogni tive state, we have measured A beta (1-40) levels and the effects of exogen ous A beta (1-40) on hippocampal ACh release in young adult as well as aged cognitively-unimpaired (AU) and -impaired (AI) rats. Endogenous levels of A beta (1-40) in the hippocampus are significantly increased in aged rats. Additionally, 10 nM A beta (1-40) potently inhibited endogenous ACh release from the hippocampus of the three groups of rats, but the time-course of t he effects clearly indicate that the cholinergic neurones of AI rats are mo re sensitive to A beta peptides than either AU or young adult rats. These r esults, together with earlier reports, suggest that the processing of the p recursor protein of A beta peptide alters with normal aging and the respons e of the cholinergic neurones to the peptide possibly varies with the cogni tive status of the animals. (C) 2001 Elsevier Science B.V. All rights reser ved.