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Peer-reviewedCC BY-NC-NDJournal of neuroinflammation

SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.

  • Yu-Ge Zhang1
  • Shi-Yao Li1
  • Yi-Zhen Hu1
  • Yi Ding2
  • Yu-Tong Zhang1
  • Hui-Wen Zhang1
  • Yong-Jie Zhang3,4,5
  • Lu Xu6
  • Zhi-Yuan Zhang7,8
  • Lei Li9,10
10 affiliations
  1. 1School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China.
  2. 2Med-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.
  3. 3Department of Human Anatomy, School of Basic Medical Sciences, Lianyungang Medical-Education Innovation and Research Center, Nanjing Medical University, Nanjing, China. [email protected].
  4. 4Department of Human Anatomy, Nanjing Medical University, Nanjing, China. [email protected].
  5. 5Human Brain Tissue Resource Center, Nanjing Medical University, Nanjing, China. [email protected].
  6. 6School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. [email protected].
  7. 7School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. [email protected].
  8. 8Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. [email protected].
  9. 9School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. [email protected].
  10. 10Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Longmian Avenue 101, Nanjing, Jiangsu, China. [email protected].
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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.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026spry1,
  title = {{SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.}},
  author = {Yu-Ge Zhang and Shi-Yao Li and Yi-Zhen Hu and Yi Ding and Yu-Tong Zhang and Hui-Wen Zhang and Yong-Jie Zhang and Lu Xu and Zhi-Yuan Zhang and Lei Li},
  journal = {Journal of neuroinflammation},
  year = {2026},
  month = jul,
  doi = {10.1186/s12974-026-03949-2},
  url = {https://europepmc.org/article/MED/42894231},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.
AU  - Yu-Ge Zhang
AU  - Shi-Yao Li
AU  - Yi-Zhen Hu
AU  - Yi Ding
AU  - Yu-Tong Zhang
AU  - Hui-Wen Zhang
AU  - Yong-Jie Zhang
AU  - Lu Xu
AU  - Zhi-Yuan Zhang
AU  - Lei Li
PY  - 2026
DA  - 2026/07/01
JO  - Journal of neuroinflammation
DO  - 10.1186/s12974-026-03949-2
UR  - https://europepmc.org/article/MED/42894231
AB  - 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.
SN  - 1742-2094
ER  -