Oligomeric Aβ-induced synaptic dysfunction in Alzheimer's disease

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.

Figure 1

Schematic diagram outlining mechanisms of oligomeric Aβ-induced synaptic dysfunction. At pathological concentrations, Aβ oligomers may interact with multiple astrocytic, microglial, and neuronal synaptic proteins, including α7-AChRs and NMDARs, triggering a series of toxic synaptic events. 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.

Figure 2

Mitochondrial impairment and synaptic dysfunction in AD. (A) Under pathological conditions, Aβ oligomers directly or indirectly affect mitochondrial fission proteins such as Drp1 and mitochondrial matrix proteins, including ABAD and CypD. Such interactions may mediate Aβ-induced mitochondrial fragmentation with consequent bioenergetics failure and resulting synaptic loss. (B) Synaptic mitochondria are more vulnerable to pathological toxins than non-synaptic mitochondria. Aβ is also more likely accumulated in synaptic mitochondria than in non-synaptic mitochondria, thus enhancing damage on synaptic mitochondria.