Loss of Fatty Acid Degradation by Astrocytic Mitochondria as a Mechanism of Neuroinflammation and Neurodegeneration

Abstract Background Astrocytes provide key neuronal support, and their phenotypic transformation is strongly implicated in neurodegenerative disorders including Alzheimer’s disease (AD). Metabolically, astrocytes possess modest mitochondrial oxidative phosphorylation (OxPhos) activity, yet the pathological role of astrocytic OxPhos in neurodegeneration remains to be defined. Method We generated the Tfam AKO mice, in which the transcription factor A mitochondrial (Tfam) is deleted selectively in astrocytes. Behavioral, electrophysiological, immunostaining, transcriptomics, metabolomics, and magnetic resonance imaging analyses were employed to characterize AD‐relevant phenotypes of Tfam AKO mice, which were further compared to an AD mouse model (5xFAD). Primary cell cultures and co‐cultures were used to determine the cell autonomous and non‐autonomous mechanisms by which disrupted astrocytic OxPhos induces astrocyte reactivity, neuroinflammation and neurodegeneration. Result Here we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of AD including reactive astrogliosis, synaptic loss, microgliosis, demyelination, and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl‐CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid‐laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia via IL‐3 signaling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Moreover, the metabolic and transcriptional signatures of the hippocampus of Tfam AKO mice highly overlap with that of 5xFAD mice. Conclusion We reveal a lipid‐centric, AD‐resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.