Journal of neuroinflammation · 2026
SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.
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Zhang Yu-Ge, Li Shi-Yao, Hu Yi-Zhen, Ding Yi, Zhang Yu-Tong, Zhang Hui-Wen, Zhang Yong-Jie, Xu Lu, Zhang Zhi-Yuan, Li Lei
Аннотация
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.
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.