Hyperactivation of the AXL-ICD/SIRT2 axis by Amyloid-β impairs astrocytic autophagic flux and exacerbates neuroinflammation

Kim, T. Y.; Bhalla, M.; Park, U. P.; Hyeon, S. J.; Hwang, I.-Y.; Seo, Y.; Youn, W.; Lee, J.-A.; Lee, J.; Lee, B.; Ryu, H.; Lee, C. J.

doi:10.64898/2026.08.23.746508

bioRxiv · 10.64898/2026.08.23.746508

Hyperactivation of the AXL-ICD/SIRT2 axis by Amyloid-β impairs astrocytic autophagic flux and exacerbates neuroinflammation

Kim, T. Y.·Bhalla, M.·Park, U. P.·Hyeon, S. J.·Hwang, I.-Y.·Seo, Y.·Youn, W.·Lee, J.-A.·Lee, J.·Lee, B.·Ryu, H.·Lee, C. J.

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Abstract

Autophagy dysfunction and neuroinflammation are central to Alzheimer's disease (AD), yet how extracellular amyloid-{beta} (A{beta}) couples to impaired autophagic flux and heightened neuroinflammation remains unknown. Here, we identify the TAM receptor AXL as a molecular transducer that couples A{beta} sensing to the regulation of autophagy and neuroinflammation in astrocytes. A{beta} induces {gamma}-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 -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 A{beta}-induced H2O2 production and astrogliosis in APP/PS1 mice. We propose the AXL-ICD/SIRT2 axis as an effective therapeutic target to reduce A{beta} burden and neuroinflammation in AD

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Kim, T. Y., Bhalla, M., Park, U. P., Hyeon, S. J., Hwang, I.-Y., Seo, Y., Youn, W., Lee, J.-A., Lee, J., Lee, B., Ryu, H., Lee, C. J.. 2026-08-27. Hyperactivation of the AXL-ICD/SIRT2 axis by Amyloid-β impairs astrocytic autophagic flux and exacerbates neuroinflammation. https://doi.org/10.64898/2026.08.23.746508

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