Interdependence of neural network dysfunction and microglial alterations in Alzheimer’s disease-related models
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Nonconvulsive epileptiform activity and microglial alterations have been detected in people with Alzheimer's disease (AD) and related mouse models. However, the relationship between these abnormalities remains to be elucidated. We suppressed epileptiform activity by treatment with the antiepileptic drug levetiracetam or by genetic ablation of tau and found that these interventions reversed or prevented aberrant microglial gene expression in brain tissues of aged human amyloid precursor protein transgenic mice, which simulate several key aspects of AD. The most robustly modulated genes included multiple factors previously implicated in AD pathogenesis, including TREM2, the hypofunction of which increases disease risk. Genetic reduction of TREM2 exacerbated epileptiform activity after mice were injected with kainate. We conclude that AD-related epileptiform activity markedly changes the molecular profile of microglia, inducing both maladaptive and adaptive alterations in their activities. Increased expression of TREM2 seems to support microglial activities that counteract this type of network dysfunction.
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This targeted microglial response is consistent with prior reports showing that tau reduction selectively modulates inflammatory and microglial transcriptional programs in amyloid models.
“This targeted response is consistent with prior reports showing that tau reduction selectively modulates inflammatory and microglial transcriptional programs in amyloid models [147].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [147]
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Cited by
Sorted by citations
Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease
Chimal-Juárez, E., Patel, H., Jury-Garfe, N., Dabin, L. C., Vidal, R., Kim, J., & Lasagna-Reeves, C. A. (2026) · bioRxiv · doi:10.64898/2026.05.12.724684
- Authors
- Das, M., Mao, W., Shao, E., Tamhankar, S., Yu, G.-Q., Yu, X., Ho, K., Wang, X., Wang, J., & Mucke, L.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Mucke, Lennart
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 24
- Issue
- 11
- Pages
- 103245
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC8561005
- OpenAlex
- W3204790500
- Cited by
- 21
- References
- 22
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 3
- FWCI
- 1.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (RF1AG063519, RR128928, UH3AG054304)
- Alzheimer's Association
- Gladstone Institutes
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, epileptiform activity, microglia, TREM2, levetiracetam, amyloid precursor protein transgenic mice, kainate-induced seizures, microglial gene expression, neural network dysfunction, antiepileptic drugs
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