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Cited by 111Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Tau binding protein CAPON induces tau aggregation and neurodegeneration

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Hashimoto, Shoko, Matsuba, Yukio, Kamano, Naoko, Mihira, Naomi, Sahara, Naruhiko, Takano, Jiro, Muramatsu, Shin-ichi, Saido, Takaomi C. +1 more·2019·Nature Communications
DOI 10.1038/s41467-019-10278-xPMC PMC6546774
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Abstract

Abstract To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the App NL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer’s disease (AD) pathogenesis, CAPON was overexpressed in the brain of App NL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.

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  • More physiological double knock-in models express humanized mutant APP and MAPT under endogenous promoters.

    “More physiological double knock‐in models express humanized mutant APP and MAPT under endogenous promoters. 73 , 74”

    From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [74]

    The Introduction describes double-knock-in mice made by crossing an App knock-in carrying familial Alzheimer’s mutations with a human MAPT knock-in. The Methods say human MAPT replaces mouse Mapt at its native locus. However, the Introduction explicitly says the human tau is wild-type, so the claim is unsupported if “mutant” is intended to describe MAPT as well as APP. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Aβ plaque accumulation does not exacerbate human WT tau pathology.

    “Interestingly, Aβ plaque accumulation does not exacerbate human WT tau pathology (7), though overexpression of a seed-competent tau fragment can induce the pathological conversion of WT mouse tau in mice with neuritic Aβ plaques (8).”

    From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [7]

    The Introduction reports that mice expressing wild-type human tau showed no overt pathological changes when crossed with amyloid-producing App knock-in mice. The Discussion also says the amyloid-producing mice do not exhibit severe tau pathology. These findings support the claim in the studied mouse models, but not the unqualified assertion that Aβ plaques do not exacerbate wild-type human tau pathology generally. (LLM, conf=0.83)

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Authors
Hashimoto, S., Matsuba, Y., Kamano, N., Mihira, N., Sahara, N., Takano, J., Muramatsu, S.-I., Saido, T. C., & Saito, T.
Affiliations
  • RIKEN Center for Brain Science (JP)
  • National Institutes for Quantum Science and Technology (JP)
  • Jichi Medical University (JP)
Corresponding author
  • Hashimoto, Shoko
  • Saido, Takaomi C.
  • Saito, Takashi
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-06-03
Volume
10
Issue
1
Pages
2394-2394
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-10278-x
PMC
PMC6546774
OpenAlex
W2948925924
Cited by
111
References
9
Citations by year
2026: 14 · 2025: 20 · 2024: 23 · 2023: 13 · 2022: 19 · 2021: 13 · 2020: 7 · 2019: 1 · 2018: 1
FWCI
6.86
Type
journal article
Language
en
Update notices
correction (2019-07-01)
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
  • The Japanese Biochemical Society
Funders
  • Japan Agency for Medical Research and Development
  • MEXT | Japan Society for the Promotion of Science
  • Uehara Memorial Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
capons, tau aggregation, tauopathy, Alzheimer's disease, neurodegeneration, neuronal nitric oxide synthase, PDZ ligand, NMDA receptor, tau phosphorylation, hippocampal atrophy, druggable targets
MeSH terms
Alzheimer Disease, Animals, Atrophy, Chromatography, Liquid, Disease Models, Animal, Hippocampus, Humans, Neurons, Mass Spectrometry, Amyloid beta-Protein Precursor, tau Proteins, Cell Death, Pyramidal Cells, Tauopathies, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Mice, Caspase 3, Gene Knock-In Techniques, Protein Aggregation, Pathological

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