Alzheimer’s Disease Amyloid β-Protein and Synaptic Function

Abstract

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 A beta disrupts synaptic mechanisms in vulnerable brain regions such as the hippocampus. Synaptic 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 A beta 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.

How dependent is synaptic plasticity on microglial phenotype?

“…One of the earliest papers reported that central administration of A inhibited LTP in area CA1 of the hippocampus (Cullen et al, 1997) and this observation was followed by several others which indicated that synthetic and naturally-occurring A oligomers, including A-derived diffusible ligands, inhibited LTP in all major afferent pathways in the hippocampus both in vivo and in vitro (Koffie et al, 2011;Ondrejcak et al, 2010;Walsh et al, 2002).…”

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

“…Although the neuropathological hallmark plaques are composed largely of fibrillar Ab, most attention has been devoted to investigating the pathophysiological role of non-fibrillar, water-soluble forms of Ab [5,6]. Considerable progress has been achieved in elucidating the disruptive actions of soluble Ab on synaptic transmission and plasticity of that transmission [7][8][9]. Extensive studies have examined how endogenous factors influence the time course and extent of the disruption of synaptic plasticity by soluble Ab, with particular emphasis on the actions of putative 'synaptotoxic' assemblies ranging from small oligomers to relatively large protofibrils.…”

PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments

“…Activity-dependent changes in the efficacy of synaptic transmission within the hippocampus are thought to be required for particular forms of memory, and interference with these changes, caused by elevated levels of Aβ, is thought to contribute to AD-associated memory impairments (31). Because PME-1 overexpression enhances Aβ-induced memory impairments, we sought to determine whether PME-1 overexpression also might enhance Aβ-induced impairment of activity-dependent synaptic plasticity.…”