{
  "abstract": "Background Microglial metabolic dysfunction is increasingly recognized as a key driver of neuroinflammation in Alzheimer’s disease (AD). However, the specific metabolic regulators linking lipid metabolism to pathological activation remain poorly defined. Methods We performed integrative transcriptomic analysis on four human AD brain datasets to identify core metabolic hubs. Sprouty homolog 1 (SPRY1) expression was examined in human post-mortem tissues, and its functional role was validated in primary microglia, Drosophila, and APP/PS1-21 mice using genetic knockdown, behavioral assays, and histological analysis. Moreover, we employed co-immunoprecipitation, mass spectrometry, and metabolic flux assays to elucidate the underlying pathways. Results We identified SPRY1 as a key hub gene upregulated in the hippocampus of AD patients and mouse models. SPRY1 was predominantly expressed in plaque-associated microglia, and specifically correlated with advancing age, Aβ load and Braak stage. Functionally, microglial SPRY1 knockdown enhanced Aβ phagocytosis, reduced pro-inflammatory cytokines, and protected neurons from Aβ-induced damage in vitro. In vivo, glial-specific knockdown of the SPRY1 homolog sty rescued cognitive and motor deficits in AD flies, while microglia-specific knockdown in mice reduced amyloidosis and neuroinflammation. Mechanistically, SPRY1 acted as a metabolic switch by retaining fatty acid transport protein 3 (FATP3) on the endoplasmic reticulum (ER). This interaction blocked FATP3 translocation to mitochondria, thereby reducing fatty acid oxidation (FAO) and promoting lipid droplet (LD) accumulation, which drives a microglial pro-inflammatory phenotype. Conclusions This study unveils a novel SPRY1-FATP3 retention mechanism that links impaired fatty acid metabolism to neuroinflammation. Targeting this axis represents a promising strategy to reprogram microglial metabolism and provide neuroprotection in AD. Graphical Abstract In AD microglia, elevated SPRY1 levels and enhanced SPRY1-FATP3 interaction reduce mitochondrial FATP3 localization, leading to decreased FAO, LD accumulation, and impaired phagocytic activity, while exacerbating inflammatory responses. SPRY1 knockdown restores FATP3 mitochondrial localization, FAO levels, and phagocytic activity while reducing inflammation, thereby improving Aβ pathology in APP/PS1-21 mice. Consistently, sty knockdown in Drosophila rescues behavioral deficits in an Aβ model.",
  "abstract_shown": true,
  "affiliations": [
    "School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China.",
    "Med-X Institute, Center for Immunological and Metabolic Diseases and Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xian, China.",
    "Department of Human Anatomy, School of Basic Medical Sciences, Lianyungang Medical-Education Innovation and Research Center, Nanjing Medical University, Nanjing, China. zhangyongjie@njmu.edu.cn.",
    "Department of Human Anatomy, Nanjing Medical University, Nanjing, China. zhangyongjie@njmu.edu.cn.",
    "Human Brain Tissue Resource Center, Nanjing Medical University, Nanjing, China. zhangyongjie@njmu.edu.cn.",
    "School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. xulu@njmu.edu.cn.",
    "School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. zzy@njmu.edu.cn.",
    "Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. zzy@njmu.edu.cn.",
    "School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. NJMULL@njmu.edu.cn.",
    "Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. NJMULL@njmu.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yu-Ge Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Shi-Yao Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Yi-Zhen Hu"
    },
    {
      "affs": [
        1
      ],
      "name": "Yi Ding"
    },
    {
      "affs": [
        0
      ],
      "name": "Yu-Tong Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Hui-Wen Zhang"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Yong-Jie Zhang"
    },
    {
      "affs": [
        5
      ],
      "name": "Lu Xu"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Zhi-Yuan Zhang"
    },
    {
      "affs": [
        8,
        9
      ],
      "name": "Lei Li",
      "orcid": "0009-0001-8486-1101"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8ah7ahb8hqj4y.bib",
  "cited_by": 0,
  "doi": "10.1186/s12974-026-03949-2",
  "fulltext_url": "https://europepmc.org/articles/PMC13679128",
  "id": "8ah7ahb8hqj4y",
  "issns": [
    "1742-2094"
  ],
  "landing_url": "https://europepmc.org/article/MED/42894231",
  "language": "eng",
  "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": [
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      "lcc",
      "RC346-429"
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      "2808|Neuroinflammation and Neurodegeneration Mechanisms"
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  "pdf_url": "https://europepmc.org/articles/PMC13679128?pdf=render",
  "pmcid": "PMC13679128",
  "pmid": "42894231",
  "published": "2026-07-01",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/8ah7ahb8hqj4y.ris",
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    {
      "first_seen": "2026-10-30T12:19:42Z",
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2808|Neuroinflammation and Neurodegeneration Mechanisms",
      "subfield": "neurology"
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  ],
  "title": "SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.",
  "title_text": "SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T14:20:47Z",
  "url": "https://research.draconitic.com/paper/8ah7ahb8hqj4y",
  "venue": "Journal of neuroinflammation",
  "versions": []
}