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Cited by 203Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

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Xu, Yilan, Zhao, Manna, Han, Yuying, Zhang, Heng·2020·Frontiers in Neuroscience
DOI 10.3389/fnins.2020.00660PMC PMC7344222
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Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically by amyloid plaques, neuronal loss, and neurofibrillary tangles. Abnormal amyloid β-protein (Aβ) deposition in the brain is often thought of as a major initiating factor in AD neuropathology. However, gamma-aminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, and Aβ decreases synaptic glutamatergic transmission to decrease neural network activity. Furthermore, there is now evidence suggesting that neural network activity is aberrantly increased in AD patients and animal models due to functional deficits in and decreased activity of GABA inhibitory interneurons, contributing to cognitive deficits. Here we describe the roles played by excitatory neurons and GABA inhibitory interneurons in Aβ-induced cognitive deficits and how altered GABA interneurons regulate AD neuropathology. We also comprehensively review recent studies on how GABA interneurons and GABA receptors can be exploited for therapeutic benefit. GABA interneurons are an emerging therapeutic target in AD, with further clinical trials urgently warranted.

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  • Evidence that FTD tau pathology leads to similar network dysfunction suggests converging network dysfunction in AD and primary tauopathies.

    “Evidence that FTD tau pathology leads to similar network dysfunction suggests converging network dysfunction in AD and primary tauopathies51–53.”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [53]

    The ‘Targets to Improve GABA Inhibitory Interneuron Activity’ section reports abnormal neural network activity in TauP301L mice and describes excitation–inhibition imbalance during AD development (page not provided). This supports a similarity in network dysfunction, but the cited paper does not establish that FTD tau pathology causes it or directly compare AD with primary tauopathies. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • FTD tau pathology leads to network dysfunction similar to that in AD, suggesting converging network dysfunction in AD and primary tauopathies.

    “The revelation that frontotemporal dementia (FTD) tau pathology led to similar network dysfunction suggests converging network dysfunction in AD and primary tauopathies49–51”

    From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [51]

    In “Targets to Improve GABA Inhibitory Interneuron Activity” (page unavailable), the review reports that mutant tau causes grid-cell dysfunction and that tau phosphorylation produces abnormal neural network activity in TauP301L mice. It does not identify these findings as FTD pathology or compare network dysfunction in FTD with AD, so the proposed convergence between AD and primary tauopathies is not established by this source. (LLM, conf=0.81)

    Experimental — accuracy not yet measured

  • Loss of inhibitory GABAergic interneurons in hippocampus has been associated with Alzheimer's disease pathology.

    “Loss of these interneurons has also been associated with Alzheimer’s disease pathology [91].”

    From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [91]

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Authors
Xu, Y., Zhao, M., Han, Y., & Zhang, H.
Affiliations
Shaoxing University (CN)
Corresponding author
Zhang, Heng
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2020-06-30
Volume
14
Pages
660-660
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2020.00660
PMC
PMC7344222
OpenAlex
W3038338923
Cited by
203
References
49
Citations by year
2026: 25 · 2025: 38 · 2024: 36 · 2023: 39 · 2022: 41 · 2021: 19 · 2020: 4
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (31800891)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, GABAergic interneurons, GABA, amyloid-beta, synaptic inhibition, glutamatergic neurotransmission, cognitive impairment, GABA receptors, therapeutic target, excitatory neurons

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