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Preprint WatchMildAugust 31st, 2026

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.

Amyloid-beta drives gamma-secretase-dependent cleavage of the TAM receptor AXL, and the resulting AXL intracellular domain acts through SIRT2 to impair astrocytic autophagic flux and worsen neuroinflammation.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The preprint places AXL upstream of astrocytic autophagy failure in Alzheimer's disease, acting through a cleaved intracellular domain and SIRT2 rather than through canonical GAS6-driven receptor tyrosine kinase signalling. Claidex holds one AXL termination, bemcentinib-axl-lung-adenocarcinoma-phase1b2-supply-termination, coded strategic_reprioritization in advanced lung adenocarcinoma. That record carries no efficacy read on AXL inhibition, so it neither supports nor undermines the neurological claim, and the disease context is unrelated. The flag is mild and is registered for graph continuity rather than contradiction. The point worth tracking is pharmacological: a mechanism running through a gamma-secretase-released intracellular domain would not necessarily be blocked by the ATP-competitive kinase inhibitors that make up the existing AXL clinical toolkit, so a programme reading this preprint as a repurposing opportunity for bemcentinib should first establish that kinase inhibition affects the proposed axis at all.

Abstract excerpt

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

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.