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.

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

“…Although plaques and tangles have traditionally been regarded as the main histopathological hallmarks of AD, a large body of evidence accumulated over the past decade suggests that soluble forms of these proteins are sufficient to trigger the development of the neurotoxicity process in AD (Berger et al., 2007; Bittner et al., 2010; Chabrier, Cheng, Castello, Green & LaFerla, 2014; Forner et al., 2017; Guerrero‐Munoz, Gerson & Castillo‐Carranza, 2015; Muller‐Schiffmann et al., 2016; Shankar et al., 2008; Spires‐Jones & Hyman, 2014; Tu, Okamoto, Lipton & Xu, 2014). These studies have clearly shown that soluble Aβ and tau oligomers are toxic to synapses and that the accumulation of these soluble isoforms correlates significantly with synaptic and memory impairments (Berger et al., 2007; Bittner et al., 2010; Chabrier et al., 2014; Forner et al., 2017; Guerrero‐Munoz et al., 2015; Muller‐Schiffmann et al., 2016; Shankar et al., 2008; Spires‐Jones & Hyman, 2014; Tu et al., 2014).…”

“…These studies have clearly shown that soluble Aβ and tau oligomers are toxic to synapses and that the accumulation of these soluble isoforms correlates significantly with synaptic and memory impairments (Berger et al., 2007; Bittner et al., 2010; Chabrier et al., 2014; Forner et al., 2017; Guerrero‐Munoz et al., 2015; Muller‐Schiffmann et al., 2016; Shankar et al., 2008; Spires‐Jones & Hyman, 2014; Tu et al., 2014). In addition, we have also demonstrated that Aβ oligomers modulate the development of tau pathology and accelerate cognitive and synaptic impairments (Chabrier et al., 2014).…”

Neurotrophin regulation of Alzheimer's disease pathology

“…However soluble Aβ oligomers are considered the more toxic species (Dahlgren et al, 2002 and can induce neurotoxicity and memory deficits in mice (Brouillette et al, 2012). A widely supported hypothesis proposes that oligomeric Aβ induces the synaptic dysfunction and the spine loss that occurs in AD (Tu et al, 2014), and closely correlates with the severity of neurodegeneration (Terry et al, 1991, McLean et al, 1999. Synaptic loss mediated by…”

“…Aβ is in turn dependent on N-methyl-D-aspartate receptor (NMDA-R) activity and mediated by dysregulated redox events, elevated cytoplasmic Ca 2+ and tau hyperphosphorylation (Shankar et al, 2007, Ittner et al, 2010, Tu et al, 2014. A parsimonious conclusion is that the BFCN-lesion induced increase in hippocampal Aβ levels is due to increased soluble Aβ which may cause synaptic transmission dysfunction and/or spine degeneration to result (either directly, or perhaps in combination with reduced ACh modulation) in MWM task memory retention impairments.…”

“…As soluble Aβ is the main culprit in AD-related synapse loss (Tu et al, 2014), and we attribute our observed increase in Aβ levels to an increase in soluble Aβ, we assessed synaptic viability in the hippocampus by looking at levels of the presynaptic protein synaptophysin, however, no differences were found irrespective of increased Aβ levels. This may be due to insensitivity to mild synaptic degeneration, or that the Aβ was impairing synaptic transmission without (yet) resulting in spine degeneration.…”