title: 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-β peptide (AβOs), toxins that accumulate in AD brains and target particular synapses. Glutamate receptors appear to be centrally involved in synaptic targeting by AβOs. Once bound to neurons, AβOs 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, AβOs 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 AβOs 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 AβOs on excitatory neurotransmission. In particular, we review evidence showing that inducing neuronal hyperpolarization via activation of inhibitory GABA(A) receptors prevents AβO-induced excitotoxicity, suggesting that this could comprise a possible therapeutic approach in AD.
authors.affiliation: Department of Basic Sciences, Faculty of Dentistry, University of Chile, Santiago, Chile. apaula@med.uchile.cl
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Paula-Lima
authors.forename: Jordano
authors.initials: J
authors.lastname: Brito-Moreira
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D017470:Receptors, Glutamate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017470:Receptors, Glutamate
keywords: AMPA receptors; Aβ oligomers; GABA receptors; NMDA receptors; d-serine; synapse dysfunction