Alzheimer's Disease Amyloid beta-Protein and Synaptic Function

作者：Ondrejcak Tomas; Klyubin Igor; Hu Neng Wei; Barry Andrew E; Cullen William K; Rowan Michael J^*

来源：NeuroMolecular Medicine, 2010, 12(1): 13-26.

DOI：10.1007/s12017-009-8091-0

• Glutamate
• Acetylcholine
• NMDA receptor
• Synaptic plasticity
• Long-term potentiation
• Long-term depression

Alzheimer's disease (AD) is characterized neuropathologically by the deposition of different forms of amyloid beta-protein (A beta) including variable amounts of soluble species that correlate with severity of dementia. The extent of synaptic loss in the brain provides the best morphological correlate of cognitive impairment in clinical AD. Animal research on the pathophysiology of AD has therefore focussed on how soluble Ab disrupts synaptic mechanisms in vulnerable brain regions such as the hippocampus. Synapic plasticity in the form of persistent activity-dependent increases or decreases in synaptic strength provide a neurophysiological substrate for hippocampal-dependent learning and memory. Acute treatment with human-derived or chemically prepared soluble A beta that contains certain oligomeric assemblies, potently and selectively disrupts synaptic plasticity causing inhibition of long-term potentiation (LTP) and enhancement of long-term depression (LTD) of glutamatergic transmission. Over time these and related actions of A beta have been implicated in reducing synaptic integrity. This review addresses the involvement of neurotransmitter intercellular signaling in mediating or modulating the synaptic plasticity disrupting actions of soluble A beta, with particular emphasis on the different roles of glutamatergic and cholinergic mechanisms. There is growing evidence to support the view that NMDA and possibly nicotinic receptors are critically involved in mediating the disruptive effect of Ab and that targeting muscarinic receptors can indirectly modulate A beta's actions. Such studies should help inform ongoing and future clinical trials of drugs acting through the glutamatergic and cholinergic systems.

• 出版日期2010-3