Abstract

Alzheimer’s disease (AD) is a devastating disease characterized by synaptic and neuronal loss in the elderly. Compelling evidence suggests that soluble amyloid-β peptide (Aβ) oligomers induce synaptic loss in AD. Aβ-induced synaptic dysfunction is dependent on overstimulation of N-methyl-D-aspartate receptors (NMDARs) resulting in aberrant activation of redox-mediated events as well as elevation of cytoplasmic Ca2+, which in turn triggers downstream pathways involving phospho-tau (p-tau), caspases, Cdk5/dynamin-related protein 1 (Drp1), calcineurin/PP2B, PP2A, Gsk-3β, Fyn, cofilin, and CaMKII and causes endocytosis of AMPA receptors (AMPARs) as well as NMDARs. Dysfunction in these pathways leads to mitochondrial dysfunction, bioenergetic compromise and consequent synaptic dysfunction and loss, impaired long-term potentiation (LTP), and cognitive decline. Evidence also suggests that Aβ may, at least in part, mediate these events by causing an aberrant rise in extrasynaptic glutamate levels by inhibiting glutamate uptake or triggering glutamate release from glial cells. Consequent extrasynaptic NMDAR (eNMDAR) overstimulation then results in synaptic dysfunction via the aforementioned pathways. Consistent with this model of Aβ-induced synaptic loss, Aβ synaptic toxicity can be partially ameliorated by the NMDAR antagonists (such as memantine and NitroMemantine). PSD-95, an important scaffolding protein that regulates synaptic distribution and activity of both NMDA and AMPA receptors, is also functionally disrupted by Aβ. PSD-95 dysregulation is likely an important intermediate step in the pathological cascade of events caused by Aβ. In summary, Aβ-induced synaptic dysfunction is a complicated process involving multiple pathways, components and biological events, and their underlying mechanisms, albeit as yet incompletely understood, may offer hope for new therapeutic avenues.

Highlights

  • Alzheimer’s disease (AD) is the most common form of dementia among the elderly

  • AD is pathologically characterized by the presence of extracellular deposition of plaques comprised of amyloid-β peptide (Aβ) peptide and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated-tau protein, accumulating evidence suggests that these abnormal protein deposits are unlikely the causative events in AD as Aβ plaque or NFT volume poorly correlate with the severity of dementia

  • Termed as Aβ-derived diffusible ligands (ADDLs), are thought to induce synaptic loss and progressive cognitive decline in AD, whereas monomers and fibrillary aggregates may be more inconsequential to pathogenesis [7]

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Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia among the elderly. It is clinically characterized by progressive memory loss and cognitive dysfunction, with the eventual inability to perform activities of daily living (ADLs). These events include aberrant activation of NMDARs (especially NR2B-containing extrasynaptic NMDARs), elevated neuronal calcium influx, calcium-dependent activation of calcineurin/PP2B and its downstream signal transduction pathways, involving cofilin, GSK-3β, CREB, and MEF2 This results in aberrant redox reactions and severing/depolymerizing F-actin, tau-hyperphosphorylation, endocytosis of AMPARs, and eventually leads to synaptic dysfunction and cognitive impairment. Tau pathology strongly correlates with mitochondrial impairment [125,130,155,156,157,158], suggesting that tau may play a role in Aβ-induced mitochondrial dysfunction It has been shown using immunoprecipitation and immunofluorescence that hyperphosphorylated tau abnormally interacts and colocalizes with the mitochondrial fission protein Drp in postmortem AD brains [158].

Conclusions
Selkoe DJ
13. Selkoe DJ
Findings
36. Yamin G
Full Text
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