ArticleCNS neuroscience & therapeutics2026
Oligodendrocyte-Targeted SGK1.1 Inhibition Alleviates White Matter Injury and Cognitive Impairment in Alzheimer's Disease via Modulation of HDAC2 Phosphorylation.
Article in CNS neuroscience & therapeutics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundWhite matter (WM) abnormalities contribute to cognitive decline in Alzheimer's disease (AD). However, the mechanisms underlying AD-associated WM vulnerability remain incompletely understood, and effective therapeutic strategies to improve WM pathology are still limited.
methodsSgk1.1-specific RNAscope combined with Olig2 immunostaining was used to assess the cellular distribution of Sgk1.1 transcripts. Oligodendrocyte-targeted adeno-associated virus (AAV)-mediated Sgk1.1 knockdown was performed in 5 × FAD mice. Sgk1.1 overexpression was conducted in primary oligodendrocyte precursor cells (OPCs) in vitro. Phosphoproteomic profiling, co-immunoprecipitation, Phos-tag Western blot, and phospho-site mutagenesis were used to identify downstream mechanisms. A bilateral common carotid artery stenosis (BCAS) model was employed to assess broader relevance.
resultsSgk1.1 mRNA was predominantly elevated in oligodendrocyte-lineage cells of 5 × FAD mice prior to overt myelin loss. Targeted knockdown of oligodendroglial Sgk1.1 ameliorated cognitive deficits, preserved myelin ultrastructure, and promoted oligodendrocyte maturation. Conversely, Sgk1.1 overexpression arrested OPC differentiation and suppressed myelin gene expression in vitro. Mechanistically, SGK1.1 promoted HDAC2 phosphorylation at S422/S424, and blocking this phosphorylation partially reversed SGK1.1-induced maturation deficits. Furthermore, oligodendrocyte-targeted Sgk1.1 overexpression exacerbated WM injury and cognitive impairment in the BCAS model.
conclusionOur findings identify oligodendrocyte-targeted SGK1.1 inhibition as a tractable therapeutic strategy to preserve WM integrity and cognitive function, and define HDAC2 S422/S424 phosphorylation as a mechanistic node linking SGK1.1 signaling to impaired myelination in AD and related demyelinating disorders.
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