Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer’s progression

Neuroinflammation is a prominent feature of Alzheimer’s disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction. [Display omitted] •Hexokinase 2, the first enzyme of glycolysis, is upregulated in Aβ plaque-associated microglia•Partial and complete loss of microglial HK2 induces differential effects on AD progression•HK2 deletion is associated with mitochondrial dysfunction and inflammation in microglia•HK2 partial antagonism targets the IKBα-NF-κB microglial pathway to exert beneficial effects Codocedo et al. find that the gene dosage of microglial HK2 displays differential effects on microglial phenotypes and AD progression. They show that HK2 can regulate inflammation through different non-metabolic activities that are dependent on its subcellular compartmentalization.