{
  "abstract": "In Alzheimer’s disease (AD), activation of the mechanistic target of rapamycin (mTOR) pathway promotes microglial neuroprotective functions by engaging multiple cell receptors. However, the relevant downstream effectors are not fully understood. mTOR complex 1 (mTORC1) promotes mRNA translation by phosphorylating and inactivating eukaryotic translation initiation factor 4E-binding protein 1 and 2 (4E-BP1/2), which are expressed in microglia. 4E-BP1 levels in cerebrospinal fluid (CSF) are elevated in AD and correlate with markers of microglial reactivity and disease progression. Using linear regression analysis, we found that elevated CSF 4E-BP1 levels strengthen the association between soluble TREM2 levels and neurodegeneration in amyloid-positive individuals. To investigate the underlying mechanism, we performed in vitro experiments demonstrating that amyloid-β inactivated 4E-BP1 in murine microglia. The mTOR-mediated inactivation is highly dependent on Spleen Tyrosine Kinase (SYK) signaling and repeated exposure to amyloid-β impaired this process, whereas prolonged exposure increased 4E-BP1 levels in microglia. Deletion of 4E-BP1/2 resulted in increased mitochondrial mass and oxidative phosphorylation, reduced pro-inflammatory signaling, and protected microglia from amyloid-induced apoptosis. Thus, impaired 4E-BP1 inactivation—due to reduced mTOR signaling or excess 4E-BP1—disrupts immune resolution, leading to metabolic exhaustion and microglial cell death. We identify the SYK–mTORC1–4E-BP1 signaling axis as a key regulator of microglial mitochondrial biogenesis and immune resolution in AD.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biochemistry and Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada",
    "Department of Biochemistry, Chungbuk National University, Cheongju 28644, South Korea",
    "Department of Clinical Sciences, Lund University, Lund 221 84, Sweden",
    "SciLifeLab, Lund 221 00, Sweden",
    "Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, South Korea",
    "Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada",
    "The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada",
    "Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 1A1, Canada",
    "Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-170, Brazil",
    "Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sara Bermudez",
      "orcid": "0009-0009-0335-4799"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jung-Hyun Choi"
    },
    {
      "affs": [
        0
      ],
      "name": "Niaz Mahmood"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Jacob W. Vogel",
      "orcid": "0000-0001-6394-9940"
    },
    {
      "affs": [
        0
      ],
      "name": "Hashem Almousa"
    },
    {
      "affs": [
        0
      ],
      "name": "Ziying Huang"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Sung-Hoon Kim"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Vivian Yuchan Zhu"
    },
    {
      "affs": [
        0,
        6
      ],
      "name": "Linqiao Zhou"
    },
    {
      "affs": [
        7
      ],
      "name": "Diana Casas-Antillon"
    },
    {
      "affs": [
        7
      ],
      "name": "Moein Yaqubi"
    },
    {
      "affs": [
        8
      ],
      "name": "Danielle Cozachenco"
    },
    {
      "affs": [
        7
      ],
      "name": "Jo Anne Stratton"
    },
    {
      "affs": [
        2
      ],
      "name": "Oskar Hansson"
    },
    {
      "affs": [
        7
      ],
      "name": "Luke Healy"
    },
    {
      "affs": [
        9
      ],
      "name": "Argel Aguilar-Valles",
      "orcid": "0000-0002-2272-1138"
    },
    {
      "affs": [
        0
      ],
      "name": "Nahum Sonenberg",
      "orcid": "0000-0002-4707-8759"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2q5jfydma23zn.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2610766123",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13715769/",
  "id": "2q5jfydma23zn",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://doi.org/10.1073/pnas.2610766123",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "424"
    ],
    [
      "heading",
      "Biological Sciences"
    ],
    [
      "heading",
      "Neuroscience"
    ],
    [
      "heading",
      "Sdg-3-Good-Health-and-Well-Being"
    ],
    [
      "openalex",
      "2808|Neuroinflammation and Neurodegeneration Mechanisms"
    ]
  ],
  "openalex": "W7223081454",
  "pdf_url": null,
  "pmcid": "PMC13715769",
  "pmid": "42905554",
  "published": "2026-10-21",
  "publisher": "National Academy of Sciences",
  "ris": "https://research.draconitic.com/paper/2q5jfydma23zn.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T12:22:58Z",
      "native_id": "PMC13715769",
      "source": "pmc",
      "url": "https://doi.org/10.1073/pnas.2610766123"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "heading:Neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins",
  "title_text": "Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:22:58Z",
  "url": "https://research.draconitic.com/paper/2q5jfydma23zn",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}