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Cited by 96Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchAlzheimer's disease research and treatments

Tau Reduction Prevents Key Features of Autism in Mouse Models

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Tai, Chao, Chang, Che-Wei, Yu, Gui-Qiu, Lopez, Isabel, Yu, Xinxing, Wang, Xin, Guo, Weikun, Mucke, Lennart·2020·Neuron
DOI 10.1016/j.neuron.2020.01.038PMC PMC7210056
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Abstract

Autism is characterized by repetitive behaviors, impaired social interactions, and communication deficits. It is a prevalent neurodevelopmental disorder, and available treatments offer little benefit. Here, we show that genetically reducing the protein tau prevents behavioral signs of autism in two mouse models simulating distinct causes of this condition. Similar to a proportion of people with autism, both models have epilepsy, abnormally enlarged brains, and overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B)/ mammalian target of rapamycin (mTOR) signaling pathway. All of these abnormalities were prevented or markedly diminished by partial or complete genetic removal of tau. We identify disinhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative PI3K regulator that tau controls, as a plausible mechanism and demonstrate that tau interacts with PTEN via tau's proline-rich domain. Our findings suggest an enabling role of tau in the pathogenesis of autism and identify tau reduction as a potential therapeutic strategy for some of the disorders that cause this condition.

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  • Tau can regulate PI3K-Akt-mTOR signaling, but under pathological stress such as in ASD or amyloid accumulation, it can promote network dysfunction.

    “Tau can regulate this pathway [56], but under pathological stress such as in conditions such as ASD or amyloid accumulation, it can promote network dysfunction [22, 143].”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [56]

    The Discussion (page not provided) proposes that tau enables abnormalities in some ASD mouse models under pathological conditions, supporting the ASD portion of the claim. Our copy does not establish the amyloid-accumulation portion; amyloid-related network impairment appears in the title of another study in the References, not as a finding of this study. The PI3K/Akt/mTOR clause is attached to a different citation in the citing sentence. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Pathogenic gain of function of tau in neurons exacerbates deleterious processes, including overstimulation of PI3K-Akt-mTOR signaling.

    “Importantly, evidence suggests that pathogenic gain of function of tau in neurons exacerbates deleterious processes, including overstimulation of PI3K-Akt-mTOR signaling [56].”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [56]

    The Results section (page unavailable) supports a role for neuronal tau in PI3K/Akt/mTOR overactivation: tau reduction lowered stimulated pAkt in neurons, and the authors propose that tau limits PTEN activity. But the Discussion (page unavailable) calls this a physiological function of tau and reports no evidence of an abnormal tau species in the ASD models studied. It does not establish the claimed pathogenic gain of function. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Tau ablation confers neuronal protection resulting in the recovery of behavioral deficits in neurodegenerative and neurodevelopmental models.

    “Numerous studies across neurodegenerative and neurodevelopmental models have shown that tau ablation confers neuronal protection resulting in the recovery of behavioral deficits [56, 75, 76, 121–123].”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [56]

    The Results (page unavailable) report that tau ablation prevented autism-like behavioral deficits and that tau reduction prevented neural abnormalities in two neurodevelopmental mouse models. The Discussion (page unavailable) mentions benefits in neurodegenerative models but does not establish neuronal protection as the cause of behavioral recovery across both types of model. This study primarily demonstrates prevention of deficits, not recovery after they develop. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In the Cntnap2-/- mouse model of autism with focal epilepsy, global tau knockdown prevents epileptic activity in addition to other autistic-like behaviors.

    “In the Cntnap2–/– mouse model of autism with focal epilepsy, global tau knockdown prevents epileptic activity in addition to other autistic-like behaviors (Tai et al., 2020), indicating an epileptogenic role of tau in ASD.”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Tai et al., 2020

    The Results section reports that complete or partial tau reduction prevented several autism-like behavioral deficits in Cntnap2−/− mice. It says tau reduction *diminished* epileptic activity, not that it prevented it. The same section identifies focal epilepsy as part of the human syndrome associated with CNTNAP2 mutations, but does not characterize the mice’s epilepsy as focal. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • In genetic mouse models of autism spectrum disorder and Dravet syndrome, tau ablation prevents epilepsy and normalizes mTOR overactivation.

    “In genetic mouse models of ASD and Dravet syndrome, tau ablation prevents epilepsy and normalizes mTOR overactivation (Gheyara et al., 2014; Tai et al., 2020; Shao et al., 2022), suggesting that reducing tau may be beneficial in these diseases via PTEN disinhibition.”

    From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Tai et al., 2020

    The Results (page unavailable) report that complete or partial tau reduction prevented overactivation of Akt and S6, markers of the mTOR pathway, in both the Dravet-syndrome and Cntnap2 autism models. The Introduction reports prevention or reduction of epilepsy in the Dravet model, but the Results say epileptic activity in Cntnap2 mice was diminished, not prevented. Thus the claim overstates the epilepsy finding across the models. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Tai, C., Chang, C.-W., Yu, G.-Q., Lopez, I., Yu, X., Wang, X., Guo, W., & Mucke, L.
Affiliations
Gladstone Institutes (US)
Corresponding author
Mucke, Lennart
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2020-05
Volume
106
Issue
3
Pages
421-437.e11
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2020.01.038
PMC
PMC7210056
OpenAlex
W3009159814
Cited by
96
References
17
Citations by year
2026: 11 · 2025: 11 · 2024: 16 · 2023: 19 · 2022: 17 · 2021: 12 · 2020: 10
FWCI
8.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
autism spectrum disorder, tau protein, PTEN, PI3K/AKT/mTOR pathway, epilepsy, brain overgrowth, proline-rich region, social interaction deficits, repetitive behavior, mouse models of autism, therapeutic target
MeSH terms
Animals, Autistic Disorder, Binding Sites, Brain, Cells, Cultured, Humans, Membrane Proteins, Mice, Inbred C57BL, Microfilament Proteins, Nerve Tissue Proteins, Protein Binding, tau Proteins, Rats, Sprague-Dawley, Phosphatidylinositol 3-Kinases, PTEN Phosphohydrolase, Mice, Rats, Proline-Rich Protein Domains, HEK293 Cells, Megalencephaly, NAV1.1 Voltage-Gated Sodium Channel

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