Upregulation of ISG15 induced by MAPT/tau accumulation represses autophagic flux by inhibiting HDAC6 activity: a vicious cycle in Alzheimer disease

Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models in vivo and in vitro. ISG15 overexpression in cells and the hippocampus inhibited HDAC6 (histone deacetylase 6) activity through C-terminal LRLRGG binding to HDAC6. Consequently, this increased CTTN (cortactin) acetylation, disrupted CTTN and F-actin recruitment to lysosomes, and impaired autophagosome (AP)-lysosome (LY) fusion. These disruptions led to MAPT/tau accumulation, synaptic damage, neuronal loss, and cognitive deficits. Conversely, ISG15 knockdown in our HsMAPT (human MAPT) pathology model restored HDAC6 activity, promoted AP-LY fusion, and improved cognitive function. This study identifies ISG15 as a key regulator of autophagic flux in AD, suggesting that targeting ISG15-mediated autophagy could offer therapeutic potential for AD.Abbreviation: AAV: adeno-associated virus; AD: Alzheimer disease; ALP: autophagy-lysosomal pathway; ANOVA: analysis of variance; AP: autophagosome; BafA1: bafilomycin A₁; CHX: cycloheximide; CQ: chloroquine; CTTN: cortactin; FC: fear conditioning; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GRIN/NMDARs: N-methyl-D-aspartate glutamate ionotropic receptor NMDA types; HDAC6: histone deacetylase 6; HEK293: human embryonic kidney 293; HsMAPT: human MAPT; IF: immunofluorescence; IHC: immunohistochemistry; IP: immunoprecipitation; ISG15: ISG15 ubiquitin like modifier; LAMP1: lysosomal associated membrane protein 1; LY: lysosome; MAPT: microtubule associated protein tau; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MWM: Morris water maze; NOR: novel object recognition; SQSTM1/p62: sequestosome 1; ZnF UBP: zinc finger ubiquitin-binding protein.