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Cited by 12Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchAlzheimer's disease research and treatments

Tau reduction attenuates autism-like features in Fmr1 knockout mice

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Zhao, Shanshan, Jiang, Xiangyu, Han, Linkun, Jiang, Yiru, Wang, Yong, Meng, Jian, Zhu, Xiang, Zhang, Xian +2 more·2023·Molecular Autism
DOI 10.1186/s13229-023-00574-1PMC PMC10629153
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Abstract

Background: Fragile X syndrome (FXS) is a leading cause of autism spectrum disorder (ASD) and resulted from a loss of the FMR1-encoded fragile X messenger ribonucleoprotein 1 (FMRP) protein due to large CGG repeat expansions in the promoter region of the FMR1 gene. The microtubule-associated protein Tau is a promising target for Tauopathic diseases and our preliminary study found that Tau protein levels were increased in the brain of Fmr1 knockout (KO) mice, a model of FXS. However, whether Tau reduction can prevent autism-like features in Fmr1 KO mice and become a novel strategy for FXS treatment remain unknown. Methods: Tau was genetically reduced in Fmr1 KO mice through crossing Fmr1± female mice with Mapt± male mice. The male offspring with different genotypes were subjected to various autism-related behavioral tests, RNA sequencing, and biochemical analysis. Fmr1 KO male mice were treated with Tau-targeting antisense oligonucleotide (ASO) and then subjected to behavioral tests and biochemical analysis. Results: Tau expression was increased in the cortex of Fmr1 KO mice. Genetically reducing Tau prevented social defects, stereotyped and repetitive behavior, and spine abnormality in Fmr1 KO mice. Tau reduction also reversed increased periodic activity and partially rescued Per1 expression reduction in Fmr1 KO mice. Moreover, Tau reduction reversed compromised P38/MAPK signaling in Fmr1 KO mice. Finally, Tau-targeting ASO also effectively alleviated autism-like phenotypes and promoted P38/MAPK signaling in Fmr1 KO mice. Limitations: Our study is limited to male mice, in agreement with the higher incidence of FXS in males than females. Whether Tau reduction also exerts protection in females deserves further scrutiny. Moreover, although Tau reduction rescues impaired P38/MAPK signaling in Fmr1 KO mice, whether this is the responsible molecular mechanism requires further determination. Conclusion: Our data indicate that Tau reduction prevents autism-like phenotypes in Fmr1 KO mice. Tau may become a new target for FXS treatment.

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  • In ASD models, tau knockdown is associated with reduced autistic-like behaviors and decreased seizure susceptibility.

    “In models of ASD, tau knockdown has been associated with reduced autistic-like behaviors and decreased seizure susceptibility [56, 80, 81].”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [80]

    The Discussion reports that genetic and antisense-mediated tau reduction alleviated social deficits and repetitive behaviors in Fmr1 knockout mice, supporting the behavioral part of the claim. The paper does not report a seizure-susceptibility outcome in those mice; its references include other studies on tau reduction and seizures, but that does not establish the claimed outcome for this study. (LLM, conf=0.87)

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  • In multiple mouse disease models, tau ablation is associated with protective effects.

    “Interestingly, in multiple mouse disease models, tau ablation has been associated with protective effects.”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [80]

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Cited by

Sorted by citations

Authors
Zhao, S., Jiang, X., Han, L., Jiang, Y., Wang, Y., Meng, J., Zhu, X., Zhang, X., Luo, H., & Zhang, Y.-W.
Affiliations
Xiamen University (CN)
Corresponding author
Zhang, Yun-wu
ORCID
Venue
Molecular Autism
Publisher
Springer Science and Business Media LLC
Published
2023-11-07
Volume
14
Issue
1
Pages
42-42
ISSN
2040-2392 (ISSN-L)
DOI
10.1186/s13229-023-00574-1
PMC
PMC10629153
OpenAlex
W4388464118
Cited by
12
References
8
Citations by year
2026: 5 · 2025: 4 · 2024: 2 · 2023: 1
FWCI
1.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Autism (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 (U21A20361)
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
tau protein, Fmr1 knockout mice, fragile X syndrome, autism spectrum disorder, antisense oligonucleotides, p38 MAPK signaling, social behavior deficits, repetitive behavior, therapeutic target
MeSH terms
Autism Spectrum Disorder, Animals, Autistic Disorder, Disease Models, Animal, Female, Fragile X Syndrome, Male, tau Proteins, Mice, Knockout, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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