Cited by 170Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Paula‐Lima, Andrea C., Brito‐Moreira, Jordano, Ferreira, Sergio T.·2013·Journal of Neurochemistry

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 Areceptors prevents AβO‐induced excitotoxicity, suggesting that this could comprise a possible therapeutic approach in AD.

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Crossref · 10.1111/jnc.12304

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  • In AD, oligomeric Aβ particles are detectable before tau aggregation and are known to impart toxic effects at the synapse, inducing synaptic dysfunction and likely causing the early manifestation of memory deficits in AD.

    “In AD, oligomeric A␤ particles are detectable before tau aggregation and are known to impart toxic effects at the synapse (reviewed in Ref. 53), inducing synaptic dysfunction and likely causing the early manifestation of memory deficits in AD.”

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Authors
Paula‐Lima, A. C., Brito‐Moreira, J., & Ferreira, S. T.
Affiliations
  • Department of Basic Sciences Faculty of Dentistry University of Chile Santiago Chile
  • Universidade Federal do Rio de Janeiro (BR)
Corresponding author
Ferreira, Sergio T.
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2013-05-28
Volume
126
Issue
2
Pages
191-202
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
OpenAlex
W2020460747
Cited by
170
References
153
Citations by year
2026: 4 · 2025: 9 · 2024: 12 · 2023: 6 · 2022: 8 · 2021: 17 · 2020: 9 · 2019: 16 · 2018: 15 · 2017: 7 · 2016: 21 · 2015: 22 · 2014: 20 · 2013: 4
FWCI
2.46
Type
journal article
Language
en
Open access
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Americanae (AECID Library) (submittedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • Universidad de Chile (submittedVersion, cc-by-nc-nd)
Funders
  • Fondecyt (11110322)
  • BNI (P-09-015F)
  • Conselho Nacional de Desenvolvimento Cientifico e Tecnológico
  • Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro
  • National Institute of Translational Neuroscience
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid-beta oligomers, excitatory neurotransmission, glutamate receptors, NMDA receptor, AMPA receptors, excitotoxicity, D-serine, calcium signaling, synaptic plasticity, GABAA receptor, neuronal hyperpolarization, treatment options
MeSH terms
Alzheimer Disease, Animals, Brain, Humans, Synaptic Transmission, Synapses, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Receptors, Glutamate, Long-Term Potentiation

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