{
  "abstract": "Accumulation of hyperphosphorylated Tau (p‐Tau) is a central driver of neurodegeneration in Alzheimer's disease (AD). Addressing the limitations of current therapeutics, we developed TP2, a small‐molecule DEPhosphorylation‐TArgeting Chimera (DEPTAC). TP2 is engineered to physically tether endogenous PP2A to Tau, facilitating targeted dephosphorylation. Mechanistically, TP2 induces ternary complex formation and potently reduces p‐Tau in neurons. Systemic administration of TP2 in distinct tauopathy mouse models (P301L and AAV‐hTau‐N368) significantly lowered brain p‐Tau levels, oligomers, and neurofibrillary tangles without altering global PP2A activity. Crucially, by rebalancing the phosphorylation of Tau, TP2 restored Tau's physiological function, as evidenced by the preservation of neuronal morphology, synaptic integrity, and microtubule stability. TP2 also ameliorated the dysregulated neuroimmune microenvironment. Consequently, TP2 treatment robustly reversed cognitive deficits in multiple behavioral paradigms. These findings establish TP2 as a promising therapeutic candidate that targets upstream pathological phosphorylation to halt neurodegeneration and restore cognitive function.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China",
    "Institute For Translational Neuroscience Nantong First People's Hospital Southeast University Nantong Jiangsu China",
    "Institute of Structural Pharmacology & TCM Chemical Biology Fujian Key Laboratory of Chinese Materia Medica College of Pharmacy Fujian University of Traditional Chinese Medicine Fuzhou China",
    "Wuya College of Innovation School of Pharmacy Key Laboratory of Structure‐Based Drug Design & Discovery Ministry of Education Shenyang Pharmaceutical University Shenyang China",
    "Department of Rehabilitation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China",
    "Department of Clinical Medicine School of Medicine Nanchang University Nanchang China",
    "Department of Pathology The First Affiliated Hospital of Zhengzhou University Zhengzhou China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Fei Sun",
      "orcid": "0000-0001-7327-1088"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Yang Liu"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Qiuzhi Zhou",
      "orcid": "0009-0005-0420-5286"
    },
    {
      "affs": [
        3
      ],
      "name": "Qingyuan Hu"
    },
    {
      "affs": [
        0
      ],
      "name": "Weixia Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yue Xiao"
    },
    {
      "affs": [
        0
      ],
      "name": "Jingfen Su"
    },
    {
      "affs": [
        5
      ],
      "name": "Guanting Liu"
    },
    {
      "affs": [
        6
      ],
      "name": "Miaomiao Sun"
    },
    {
      "affs": [
        3
      ],
      "name": "Lixia Chen",
      "orcid": "0000-0003-2196-1428"
    },
    {
      "affs": [
        2
      ],
      "name": "Hua Li",
      "orcid": "0000-0003-1903-836X"
    },
    {
      "affs": [
        0
      ],
      "name": "Ying Yang",
      "orcid": "0000-0002-9479-4766"
    },
    {
      "affs": [
        0
      ],
      "name": "Jian‐Zhi Wang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dz9k16rscsv9j.bib",
  "cited_by": 0,
  "doi": "10.1002/advs.77088",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13460270/",
  "id": "dz9k16rscsv9j",
  "issns": [
    "2198-3844"
  ],
  "landing_url": "https://doi.org/10.1002/advs.77088",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7202174014",
  "pdf_url": null,
  "pmcid": "PMC13460270",
  "pmid": "42579441",
  "published": "2026-08-11",
  "publisher": "Wiley",
  "ris": "https://research.draconitic.com/paper/dz9k16rscsv9j.ris",
  "sources": [
    {
      "first_seen": "2026-11-06T12:23:11Z",
      "native_id": "PMC13460270",
      "source": "pmc",
      "url": "https://doi.org/10.1002/advs.77088"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "A Small‐Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau",
  "title_text": "A Small‐Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:20:29Z",
  "url": "https://research.draconitic.com/paper/dz9k16rscsv9j",
  "venue": "Advanced Science",
  "versions": []
}