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Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer’s disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunct...

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Autores principales: Meftah, Soraya, Gan, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10033629/
https://www.ncbi.nlm.nih.gov/pubmed/36970154
http://dx.doi.org/10.3389/fnsyn.2023.1129036
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author Meftah, Soraya
Gan, Jian
author_facet Meftah, Soraya
Gan, Jian
author_sort Meftah, Soraya
collection PubMed
description The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer’s disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer’s disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer’s disease. There is also growing evidence that these two proteins may have a synergistic effect on neurophysiological dysfunction. Here, we review some of the main findings of synaptic alterations in Alzheimer’s disease, and what we know from Alzheimer’s disease animal and cellular models. First, we briefly summarize some of the human evidence to suggest that synapses are altered, including how this relates to network activity. Subsequently, animal and cellular models of Alzheimer’s disease are considered, highlighting mouse models of amyloid and tau pathology and the role these proteins may play in synaptic dysfunction, either in isolation or examining how the two pathologies may interact in dysfunction. This specifically focuses on neurophysiological function and dysfunction observed within these animal models, typically measured using electrophysiology or calcium imaging. Following synaptic dysfunction and loss, it would be impossible to imagine that this would not alter oscillatory activity within the brain. Therefore, this review also discusses how this may underpin some of the aberrant oscillatory patterns seen in animal models of Alzheimer’s disease and human patients. Finally, an overview of some key directions and considerations in the field of synaptic dysfunction in Alzheimer’s disease is covered. This includes current therapeutics that are targeted specifically at synaptic dysfunction, but also methods that modulate activity to rescue aberrant oscillatory patterns. Other important future avenues of note in this field include the role of non-neuronal cell types such as astrocytes and microglia, and mechanisms of dysfunction independent of amyloid and tau in Alzheimer’s disease. The synapse will certainly continue to be an important target within Alzheimer’s disease for the foreseeable future.
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spelling pubmed-100336292023-03-24 Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression Meftah, Soraya Gan, Jian Front Synaptic Neurosci Neuroscience The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer’s disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer’s disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer’s disease. There is also growing evidence that these two proteins may have a synergistic effect on neurophysiological dysfunction. Here, we review some of the main findings of synaptic alterations in Alzheimer’s disease, and what we know from Alzheimer’s disease animal and cellular models. First, we briefly summarize some of the human evidence to suggest that synapses are altered, including how this relates to network activity. Subsequently, animal and cellular models of Alzheimer’s disease are considered, highlighting mouse models of amyloid and tau pathology and the role these proteins may play in synaptic dysfunction, either in isolation or examining how the two pathologies may interact in dysfunction. This specifically focuses on neurophysiological function and dysfunction observed within these animal models, typically measured using electrophysiology or calcium imaging. Following synaptic dysfunction and loss, it would be impossible to imagine that this would not alter oscillatory activity within the brain. Therefore, this review also discusses how this may underpin some of the aberrant oscillatory patterns seen in animal models of Alzheimer’s disease and human patients. Finally, an overview of some key directions and considerations in the field of synaptic dysfunction in Alzheimer’s disease is covered. This includes current therapeutics that are targeted specifically at synaptic dysfunction, but also methods that modulate activity to rescue aberrant oscillatory patterns. Other important future avenues of note in this field include the role of non-neuronal cell types such as astrocytes and microglia, and mechanisms of dysfunction independent of amyloid and tau in Alzheimer’s disease. The synapse will certainly continue to be an important target within Alzheimer’s disease for the foreseeable future. Frontiers Media S.A. 2023-03-09 /pmc/articles/PMC10033629/ /pubmed/36970154 http://dx.doi.org/10.3389/fnsyn.2023.1129036 Text en Copyright © 2023 Meftah and Gan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Meftah, Soraya
Gan, Jian
Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression
title Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression
title_full Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression
title_fullStr Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression
title_full_unstemmed Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression
title_short Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression
title_sort alzheimer’s disease as a synaptopathy: evidence for dysfunction of synapses during disease progression
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10033629/
https://www.ncbi.nlm.nih.gov/pubmed/36970154
http://dx.doi.org/10.3389/fnsyn.2023.1129036
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