Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease

Abstract

Alzheimer′s disease (AD) is the most common form of dementia in the elderly. Memory loss in AD is increasingly attributed to soluble oligomers of the amyloid-b peptide (AbOs), toxins that accumulate in AD brains and target particular synapses. Glutamate receptors appear to be centrally involved in synaptic targeting by AbOs. Once bound to neurons, AbOs dysregulate the activity and reduce the surface expression of both N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) types of glutamate receptors, impairing signaling pathways involved in synaptic plasticity. In the extracellular milieu, AbOs promote accumulation of the excitatory amino acids, glutamate and D-serine. This leads to overactivation of glutamate receptors, triggering abnormal calcium signals with noxious impacts on neurons. Here, we review key findings linking AbOs to deregulated glutamate neurotransmission and implicating this as a primary mechanism of synapse failure in AD. We also discuss strategies to counteract the impact of AbOs on excitatory neurotransmission. In particular, we review evidence showing that inducing neuronal hyperpolarization via activation of inhibitory GABA A receptors prevents AbOinduced excitotoxicity, suggesting that this could comprise a possible therapeutic approach in AD.

d-serine levels in Alzheimer’s disease: implications for novel biomarker development

“…12, 13, 14, 15, 16, 17 Accordingly, memantine (an open-channel blocker of NMDARs) has been approved for clinical use in patients with moderate-to-severe AD. 18 d -serine is the main co-agonist at NMDARs in frontal brain areas 19, 20, 21 and has been implicated in NMDAR-mediated neurotoxicity.…”

Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism Is Not a Major Determining Factor in the Development of Sporadic Alzheimer Disease: Evidence from an Updated Meta-Analysis

“…One of the proposed mechanisms for SAD is the amyloid hypothesis, which suggests that deposition of beta-amyloid (Aβ) is a primary event in the pathological cascade for SAD [4]. The balance between the expression and the degradation of Aβ changes, and aggregate of Aβ would cause complex reactions, such as phosphorylation of protein Tau [5], loss of neurotransmitter [6] and finally formation of senile plaques (SP), as well as intracellular neurofibrillary tangles.…”

Astrocyte-mediated metaplasticity in the hippocampus: Help or hindrance?

“…No studies have yet demonstrated a conclusive elevation in astrocytic production of D-Serine itself in schizophrenia, and genetic mutations common to this disorder are in fact correlated with diminished levels of astrocytic D-Serine in animal models (Ma et al, 2013, Abazyan et al, 2014. In contrast to schizophrenia, conditions such as Alzheimer's disease and epilepsy are characterised by increased levels of serine racemase and D-Serine in hippocampus, and subsequent overactivation of NMDARs (Ryu et al, 2010, Clasadonte et al, 2013, Paula-Lima et al, 2013, Madeira et al, 2015.…”