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Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: Emerging mechanisms

Benarroch, Eduardo E.·2018·Neurology
DOI 10.1212/wnl.0000000000005807
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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 w…

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Metadata

Authors
Benarroch, E. E.
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-07-17
Volume
91
Issue
3
Pages
125-132
ISSN
  • 0028-3878
  • 1526-632X
DOI
10.1212/wnl.0000000000005807
Cited by
115
References
16
Language
en

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CoChat. (2026). Citation check: Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: Emerging mechanisms. https://app.cochat.ai/papers/10.1212/wnl.0000000000005807
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Benarroch, E. E. (2018). Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: Emerging mechanisms. Neurology. https://doi.org/10.1212/wnl.0000000000005807