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Cited by 45Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsAmyotrophic Lateral Sclerosis Research

Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy

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Ono, Maiko, Komatsu, Masaaki, Ji, Bin, Takado, Yuhei, Shimojo, Masafumi, Minamihisamatsu, Takeharu, Warabi, Eiji, Yanagawa, Toru +6 more·2022·Aging Cell
DOI 10.1111/acel.13615PMC PMC9282839
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Abstract

Intracellular accumulation of filamentous tau aggregates with progressive neuronal loss is a common characteristic of tauopathies. Although the neurodegenerative mechanism of tau‐associated pathology remains unclear, molecular elements capable of degrading and/or sequestering neurotoxic tau species may suppress neurodegenerative progression. Here, we provide evidence that p62/SQSTM1, a ubiquitinated cargo receptor for selective autophagy, acts protectively against neuronal death and neuroinflammation provoked by abnormal tau accumulation. P301S mutant tau transgenic mice (line PS19) exhibited accumulation of neurofibrillary tangles with localization of p62 mostly in the brainstem, but neuronal loss with few neurofibrillary tangles in the hippocampus. In the hippocampus of PS19 mice, the p62 level was lower compared to the brainstem, and punctate accumulation of phosphorylated tau unaccompanied by co‐localization of p62 was observed. In PS19 mice deficient in p62 (PS19/p62‐KO), increased accumulation of phosphorylated tau, acceleration of neuronal loss, and exacerbation of neuroinflammation were observed in the hippocampus as compared with PS19 mice. In addition, increase of abnormal tau and neuroinflammation were observed in the brainstem of PS19/p62‐KO. Immunostaining and dot‐blot analysis with an antibody selectively recognizing tau dimers and higher‐order oligomers revealed that oligomeric tau species in PS19/p62‐KO mice were significantly accumulated as compared to PS19 mice, suggesting the requirement of p62 to eliminate disease‐related oligomeric tau species. Our findings indicated that p62 exerts neuroprotection against tau pathologies by eliminating neurotoxic tau species, suggesting that the manipulative p62 and selective autophagy may provide an intrinsic therapy for the treatment of tauopathy.

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  • Consistent levels of human tau expression across the lifespan of PS19 mice have been reported in plasma, whole brain, and brain subregions including brainstem and hippocampus.

    “Consistent levels of human tau expression across the lifespan of PS19 mice have also been reported in plasma, whole brain (Sun et al., 2020), and brain subregions including brainstem and hippocampus (Ono et al., 2022).”

    From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Ono et al., 2022

    The Results (Figure 1f,h; page not specified) report similar human P301S tau expression levels in the hippocampus and brainstem of PS19 mice. Figure 1 describes samples at 4 and 10 months, but the text does not establish consistent expression across the lifespan. The plasma and whole-brain claims are not attributed to Ono et al. in the citing sentence. (LLM, conf=0.82)

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Authors
Ono, M., Komatsu, M., Ji, B., Takado, Y., Shimojo, M., Minamihisamatsu, T., Warabi, E., Yanagawa, T., Matsumoto, G., Aoki, I., Kanaan, N. M., Suhara, T., Sahara, N., & Higuchi, M.
Affiliations
  • National Institutes for Quantum Science and Technology (JP)
  • Juntendo University (JP)
  • Fudan University (CN)
  • University of Tsukuba (JP)
  • Nagasaki University (JP)
  • Michigan State University (US)
Corresponding author
  • Ono, Maiko
  • Sahara, Naruhiko
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2022-06-05
Volume
21
Issue
7
Pages
e13615-e13615
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.13615
PMC
PMC9282839
OpenAlex
W4282052794
Cited by
45
References
7
Citations by year
2026: 4 · 2025: 9 · 2024: 20 · 2023: 11 · 2022: 1
FWCI
6.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • QST-Repository (National Institutes for Quantum and Radiological Science and Technology) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (NIH AG044372, NIH NS081730)
  • Japan Society for the Promotion of Science (JP19K06896, JP21H00446, JP26117011)
  • Japan Agency for Medical Research and Development (JP19dk0207049, JP21dm0207072, JP21dk0207046)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
p62, tauopathy, tau aggregation, selective autophagy, neuroinflammation, neuronal cell death, neurofibrillary tangles, tau oligomers, neuroprotection, hippocampus, brainstem, tau phosphorylation, neurodegeneration
MeSH terms
Sequestosome-1 Protein, Animals, Disease Models, Animal, Mice, Transgenic, Neurofibrillary Tangles, tau Proteins, Tauopathies, Mice

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