A mechanistic hypothesis for the impairment of synaptic plasticity by soluble A β oligomers from Alzheimer’s brain

This review summarized AD brain ‐derived soluble Aβ oligomers (principally small, diffusible oligomers) could disrupt synaptic plasticity, by binding to membranes and changing excitatory–inhibitory balance, perturbing cellular prion protein and mGluR, down‐regulating glutamate transporters, activating cytokines and associat ed inflammatory mediators, and causing LTP inhibition and LTD facilitation. We synthesize these emerging data into a mechanistic hypothesis for synaptic failure in AD that can be modified as new knowledge is added and specific therapeutics are developed. AbstractIt is increasingly accepted that early cognitive impairment in Alzheimer's disease results in considerable part from synaptic dysfunction caused by the accumulation of a range of oligomeric assemblies of amyloid β‐protein (Aβ). Most studies have used synthetic Aβ peptides to explore the mechanisms of memory deficits in rodent models, but recent work suggests that Aβ assemblies isolated from human (AD) brain tissue are far more potent and disease‐relevant. Although reductionist experiments show Aβ o ligomers to impair synaptic plasticity and neuronal viability, the responsible mechanisms are only partly understood. Glutamatergic receptors, GABAergic receptors, nicotinic receptors, insulin receptors, the cellular prion protein, inflammatory mediators, and diverse signaling pathways have all been suggested. Studies using AD brain‐derived soluble Aβ oligomers suggest that only certai...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: REVIEW Source Type: research