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

Amyloid-β (Aβ) plays a key role in Alzheimer's disease by inducing autophagy dysfunction and neuroinflammation in astrocytes. The TAM receptor AXL serves as a molecular conduit linking Aβ sensing to the regulation of autophagy and inflammation in astrocytes. Aβ triggers the cleavage of AXL through γ-secretase, resulting in the generation of a nuclear intracellular domain (AXL-ICD).

This AXL-ICD then forms phase-separated condensates and activates autophagy gene transcription through SIRT2-mediated recruitment of the RUVBL1/2-INO80 chromatin-remodeling complex. AXL-ICD also binds to SIRT2's catalytic domain, inhibiting its deacetylase activity and increasing -tubulin acetylation, which distorts microtubule dynamics.

Moderate levels of AXL-ICD promote autophagic flux, but excessive accumulation paradoxically leads to microtubule hyperstabilization, impeding autophagosome-lysosome fusion and causing the pathological buildup of autophagosomes and hydrogen peroxide (H2O2). The inhibitory peptide AxSBiP interferes with the AXL-ICD/SIRT2 interaction, restores autophagic flux, lowers plaque accumulation, and normalizes Aβ-induced H2O2 production and astrogliosis in APP/PS1 mice.

The researchers suggest that the AXL-ICD/SIRT2 axis presents a promising therapeutic target to reduce Aβ burden and neuroinflammation in Alzheimer's disease.