Autophagy dysfunction and neuroinflammation are central to Alzheimer’s disease (AD), yet how extracellular amyloid-β (Aβ) couples to impaired autophagic flux and heightened neuroinflammation remains unknown. Here, we identify the TAM receptor AXL as a molecular transducer that couples Aβ sensing to the regulation of autophagy and neuroinflammation in astrocytes. Aβ induces γ-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 α-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 Aβ-induced H2O2 production and astrogliosis in APP/PS1 mice. We propose the AXL-ICD/SIRT2 axis as an effective therapeutic target to reduce Aβ burden and neuroinflammation in AD.
T. Kim, Mridula Bhalla, Uiyeol Park et al.· bioRxiv· 0 citations
Alzheimer’s disease (AD) is a major cause of dementia and a prevalent age-related neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. Although metabolic activation or dysfunction of microglia is implicated in AD pathogenesis, the phospholipid metabolism–associated signaling mechanisms within microglia remain poorly defined. In this study, we demonstrate that quinolinic acid (QA), a byproduct of tryptophan catabolism via the kynurenine pathway, activates the microglial Kennedy pathway—responsible for de novo phosphatidylethanolamine (PE) biosynthesis—by upregulating the enzymes EPT1 and ETNK1. This activation markedly enhances the synthesis of PE species enriched in polyunsaturated fatty acids. Concurrently, QA significantly increases the expression of gamma-aminobutyric acid receptor–associated protein (GABARAP), promotes its lipidation, and facilitates the GABARAP-associated phagocytosis (GAP) of Aβ oligomers by microglia. Knockdown of EPT1 and ETNK1 attenuated QA-induced PE synthesis and impaired the GAP of Aβ oligomers, whereas inhibition of GABARAP lipidation via STBD1 deconjugase substantially reduced QA-mediated GAP. QA administration upregulated microglial Gabarap expression and decreased the Aβ plaque burden in the hippocampus of AD (5xFAD) mice, whereas Gabarap knockdown abrogated QA-induced microglial clearance of Aβ. Collectively, these findings reveal a paradoxically beneficial role of QA in activating a microglia-specific signaling cascade that promotes PE biosynthesis and GAP, thereby enhancing Aβ clearance and mitigating AD pathology. Targeting the microglial PE synthesis pathway and GAP may represent a promising therapeutic strategy to ameliorate Aβ accumulation and slow AD progression.
Seung Jae Hyeon, Seungchan Kim, Jiyeon Chu et al.· Signal Transduction and Targ...· 1 citation
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