Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: Emerging mechanisms.

Abstract

Impaired synaptic plasticity and dendritic loss in excitatory glutamatergic synapses are early events in Alzheimer disease (AD). These synaptic abnormalities are triggered by accumulation of soluble fibrillary β-amyloid (Aβ) oligomers, which bind to several postsynaptic and presynaptic partners. Many of the synaptic effects of Aβ oligomers involve NMDA receptors (NMDARs) and type 1 metabotropic glutamate receptor 5 (mGluR5). These receptors mediate use-dependent plasticity of glutamatergic synapses in the hippocampus and other brain regions. Synaptic plasticity includes long-term potentiation (LTP) and long-term depression (LTD) of efficacy of synaptic transmission. Studies both in vitro and in animal models indicate that Aβ oligomers disrupt LTP and promote LTD; these effects are associated with decreased density of dendritic spines. The mechanisms by which Aβ oligomers elicit these synaptic changes are similar to those normally utilized in the CNS during development and learning. In addition, interactions of β oligomers with extrasynaptic NMDARs and mGluR5 promote tau-hyperphosphorylation, leading to impaired mitochondrial transport to synapses and thus disrupting calcium homeostasis and energy-dependent processes. Via activation of glial cells, Aβ triggers complement-mediated pruning of vulnerable synapses. Loss of dendritic spines precedes the accumulation of neuritic plaques and neurofibrillary tangles and is potentially reversible. The multiple potential mechanisms by which Aβ oligomers may trigger dysfunction and loss of glutamatergic synapses provide multiple targets for neuroprotective therapy. There are several reviews focused on these topics.1–11 Only selected aspects of synaptic plasticity and its involvement in AD are reviewed here.