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Cited by 96Alzheimer's disease research and treatmentsNeurogenesis and neuroplasticity mechanismsNeuroinflammation and Neurodegeneration Mechanisms

MEF2 is a Key Regulator of Cognitive Potential and Confers Resilience to Neurodegeneration

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Barker, Scarlett J., Raju, Ravikiran M., Milman, Noah E.P., Wang, Jun, Davila-Velderrain, Jose, Gunter-Rahman, Fatima, Parro, Cameron C., Bozzelli, P. Lorenzo +5 more·2021·Science Translational Medicine
DOI 10.1126/scitranslmed.abd7695PMC PMC9258338
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Abstract

Mef2 is induced after enrichment in mice, reduces disease-associated hyperexcitability, and is a feature of cognitive resilience in patients with AD.

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Crossref · 10.1126/scitranslmed.abd7695

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  • Microglial activation and functional changes in cortical and hippocampal regions during Alzheimer's disease pathology may be ameliorated through transcriptional remodeling within microglia.

    “microglial activation and functional changes, prominently observed in cortical and hippocampal regions during Alzheimer's disease pathology, may be ameliorated through transcriptional remodeling within microglia”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [49]

    In Results, Subhead 5 (page unavailable), the paper reports differences in microglial gene expression between cognitively resilient and non-resilient individuals. But it finds no enrichment of MEF2 targets in microglial subclusters and identifies the resilience-associated MEF2 transcriptional activity as specific to excitatory neurons, not microglia. It does not report amelioration of microglial activation in cortical or hippocampal regions. (LLM, conf=0.84)

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  • AAV-induced overexpression of neuronal Mef2a/c improved cognitive function in the fear conditioning test and reduced hyperexcitability in a tauopathy mouse model.

    “Conversely, AAV‐induced overexpression of neuronal Mef2a/c improved cognitive function in the fear conditioning test and reduced hyperexcitability in a tauopathy mouse model [49].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [49]

    Results, subhead 6, reports that AAV-mediated Mef2a/c overexpression accelerated fear-memory extinction in PS19 tauopathy mice, although initial memory acquisition did not differ. The reduced neuronal hyperexcitability was measured in PS19 mice overexpressing Mef2a/c using a lentiviral construct, not the AAV construct, so the claim attributes that result to the wrong delivery method. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In PS19 (P301S) mice at 6 months of age, AAV-induced Mef2a/c overexpression decreases hyperexcitability in the prefrontal cortex.

    “Mef2a/c overexpression = > cognition↑, hyperexcitability↓”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [49]

    The Results (Subhead 6; page not available) report reduced action-potential firing in PFC neurons of PS19 mice overexpressing Mef2a/c. However, those recordings used a lentiviral construct, not AAV. The stated age of 6 months applies to the fear-extinction experiment; the passage does not specify that age for the electrophysiology recordings. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • In PS19 (P301S) mice at 6 months of age, AAV-induced Mef2a/c overexpression increases cognition in the prefrontal cortex.

    “Mef2a/c overexpression = > cognition↑, hyperexcitability↓”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [49]

    In Results, Subhead 6, the paper reports that six-month-old PS19 (P301S) mice given an AAV construct to overexpress Mef2a/c showed faster fear-memory extinction than controls. This supports the cognitive improvement, but cognition was assessed by behavior, not measured specifically in the prefrontal cortex. The prefrontal-cortex recordings reported in the same section used a lentiviral construct to assess neuronal excitability. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cites

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Authors
Barker, S. J., Raju, R. M., Milman, N. E. P., Wang, J., Davila-Velderrain, J., Gunter-Rahman, F., Parro, C. C., Bozzelli, P. L., Abdurrob, F., Abdelaal, K., Bennett, D. A., Kellis, M., & Tsai, L.-H.
Affiliations
  • Massachusetts Institute of Technology (US)
  • Boston Children's Hospital (US)
  • Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Rush University Medical Center (US)
  • Broad Institute (US)
Corresponding author
  • Barker, Scarlett J.
  • Raju, Ravikiran M.
  • Tsai, Li-Huei
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-11-03
Volume
13
Issue
618
Pages
eabd7695-eabd7695
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.abd7695
PMC
PMC9258338
OpenAlex
W3208857745
Cited by
96
References
10
Citations by year
2026: 12 · 2025: 25 · 2024: 27 · 2023: 23 · 2022: 9
FWCI
9.27
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG017917, R01AG058002, R01AG062335, RF1AG054012, R01AG015819, P30AG010161, R01AG046174, RF1AG054321, U01AG061356, P30AG072975)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD098061)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
MEF2, transcription factors, cognitive reserve, neurodegeneration, tauopathy, cognitive flexibility, neuronal hyperexcitability, healthy aging, biomarkers, therapeutic target
MeSH terms
Animals, Brain, Cognition, Humans, Neurodegenerative Diseases, Mice, Gene Regulatory Networks, MEF2 Transcription Factors

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