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Cited by 401Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

Neuronal hyperexcitability in Alzheimer's disease: what are the drivers behind this aberrant phenotype?

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Targa Dias Anastacio, Helena, Matosin, Natalie, Ooi, Lezanne·2022·Translational Psychiatry
DOI 10.1038/s41398-022-02024-7PMC PMC9217953
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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to loss of cognitive abilities and ultimately, death. With no cure available, limited treatments mostly focus on symptom management. Identifying early changes in the disease course may provide new therapeutic targets to halt or reverse disease progression. Clinical studies have shown that cortical and hippocampal hyperactivity are a feature shared by patients in the early stages of disease, progressing to hypoactivity during later stages of neurodegeneration. The exact mechanisms causing neuronal excitability changes are not fully characterized; however, animal and cell models have provided insights into some of the factors involved in this phenotype. In this review, we summarize the evidence for neuronal excitability changes over the course of AD onset and progression and the molecular mechanisms underpinning these differences. Specifically, we discuss contributors to aberrant neuronal excitability, including abnormal levels of intracellular Ca 2+ and glutamate, pathological amyloid β (Aβ) and tau, genetic risk factors, including APOE , and impaired inhibitory interneuron and glial function. In light of recent research indicating hyperexcitability could be a predictive marker of cognitive dysfunction, we further argue that the hyperexcitability phenotype could be leveraged to improve the diagnosis and treatment of AD, and present potential targets for future AD treatment development.

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  • Hippocampal hyperexcitability is a key feature of early AD and contributes to cognitive decline throughout disease progression.

    “Hippocampal hyperexcitability is a key feature of early AD and contributes to cognitive decline throughout disease progression (Targa Dias Anastacio et al., 2022).”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Targa Dias Anastacio et al., 2022

    The Abstract and “Evidence of neuronal network hyperactivity from human studies” describe hippocampal hyperactivity in early AD. The “Is hyperexcitability neuroprotective or neurodegenerative?” section links increased activity to AD pathology and cognitive deficits, but the Abstract says hyperactivity progresses to hypoactivity in later stages; the source does not establish that hippocampal hyperexcitability contributes to decline throughout progression. Page numbers were not provided in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • A cascade of events following cytokine alterations may result in hyperexcitability of the neuronal network, which is important in the pathophysiology of Alzheimer's disease.

    “This cascade of events may result in hyperexcitability of the neuronal network, which is important in the pathophysiology of AD (Clarkson et al., 2017; Targa Dias Anastacio, Matosin and Ooi, 2022).”

    From Arbovirus infection increases the risk for the development of neurodegenerative disease pathology in the murine model (2024) · cites this paper as Targa Dias Anastacio, Matosin and Ooi, 2022

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Authors
Targa Dias Anastacio, H., Matosin, N., & Ooi, L.
Affiliations
University of Wollongong (AU)
Corresponding author
Ooi, Lezanne
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-06-22
Volume
12
Issue
1
Pages
257-257
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-022-02024-7
PMC
PMC9217953
OpenAlex
W4283387616
Cited by
401
References
170
Citations by year
2026: 123 · 2025: 129 · 2024: 96 · 2023: 45 · 2022: 8
FWCI
9.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Online (University of Wollongong) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion)
Funders
  • Department of Health | National Health and Medical Research Council (APP1135720, APP1105445)
  • Rebecca L. Cooper Medical Research Foundation (#F2021971, #PG2020645)
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, neuronal hyperexcitability, cortical hyperactivity, hippocampal hyperactivity, intracellular calcium, glutamate, amyloid-beta, tau pathology, apolipoprotein E, inhibitory interneurons, glial dysfunction, early Alzheimer's disease, cognitive impairment, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Hippocampus, Humans, Neurons, Phenotype, Amyloid beta-Peptides

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