{
  "abstract": "Autophagy dysfunction and neuroinflammation are central to Alzheimer's disease (AD), yet how extracellular amyloid-{beta} (A{beta}) couples to impaired autophagic flux and heightened neuroinflammation remains unknown. Here, we identify the TAM receptor AXL as a molecular transducer that couples A{beta} sensing to the regulation of autophagy and neuroinflammation in astrocytes. A{beta} induces {gamma}-secretase-dependent cleavage of AXL, generating a nuclear intracellular domain (AXL-ICD) that forms phase-separated condensates and activates autophagy gene transcription through SIRT2-mediated recruitment of the RUVBL1/2-INO80 chromatin-remodeling complex. This axis is activated in astrocytes of postmortem AD brains. Concurrently, AXL-ICD binds to the SIRT2 catalytic domain and suppresses its deacetylase activity, increasing -tubulin acetylation and altering microtubule dynamics. While moderate AXL-ICD levels promote autophagic flux, excessive elevation paradoxically triggers microtubule hyperstabilization, thereby impairing autophagosome-lysosome fusion and causing pathological accumulation of autophagosomes and H2O2. The inhibitory peptide AxSBiP disrupts the AXL-ICD/SIRT2 interaction, restores autophagic flux, reduces plaque burden, and normalizes A{beta}-induced H2O2 production and astrogliosis in APP/PS1 mice. We propose the AXL-ICD/SIRT2 axis as an effective therapeutic target to reduce A{beta} burden and neuroinflammation in AD",
  "abstract_shown": true,
  "affiliations": [
    "Institute for Basic Sciences"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "T. Y. Kim"
    },
    {
      "name": "M. Bhalla"
    },
    {
      "name": "U. P. Park"
    },
    {
      "name": "S. J. Hyeon"
    },
    {
      "name": "I.-Y. Hwang"
    },
    {
      "name": "Y. Seo"
    },
    {
      "name": "W. Youn"
    },
    {
      "affs": [
        0
      ],
      "name": "J.-A. Lee"
    },
    {
      "affs": [
        0
      ],
      "name": "J. Lee"
    },
    {
      "affs": [
        0
      ],
      "name": "B. Lee"
    },
    {
      "name": "H. Ryu"
    },
    {
      "affs": [
        0
      ],
      "name": "C. J. Lee"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/93fnwn94rdvj2.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.23.746508",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.23.746508v2.full",
  "id": "93fnwn94rdvj2",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.23.746508v2",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7204446112",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.23.746508v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-23",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/93fnwn94rdvj2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.64898/2026.08.23.746508",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.23.746508v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Hyperactivation of the AXL-ICD/SIRT2 axis by Amyloid-β impairs astrocytic autophagic flux and exacerbates neuroinflammation",
  "title_text": "Hyperactivation of the AXL-ICD/SIRT2 axis by Amyloid-β impairs astrocytic autophagic flux and exacerbates neuroinflammation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:17Z",
  "url": "https://research.draconitic.com/paper/93fnwn94rdvj2",
  "venue": "bioRxiv",
  "versions": []
}