Therapeutic targeting of immunometabolism in Alzheimer’s disease reveals a critical reliance on Hexokinase 2 dosage on microglial activation and disease progression

Summary Microgliosis and neuroinflammation are prominent features of Alzheimer’s disease (AD). Disease-responsive microglia meet their increased energy demand by reprogramming metabolism, specifically, switching to favor glycolysis over oxidative phosphorylation. Thus, targeting of microglial immunometabolism might be of therapeutic benefit for treating AD, providing novel and often well understood immune pathways and their newly recognized actions in AD. We report that in the brains of 5xFAD mice and postmortem brains of AD patients, we found a significant increase in the levels of Hexokinase 2 (HK2), an enzyme that supports inflammatory responses by rapidly increasing glycolysis. Moreover, binding of HK2 to mitochondria has been reported to regulate inflammation by preventing mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that its inflammatory role extends beyond its glycolytic activity. Here we report, that HK2 antagonism selectively affects microglial phenotypes and disease progression in a gene-dose dependent manner. Paradoxically, complete loss of HK2 fails to improve AD progression by exacerbating inflammasome activity while its haploinsufficiency results in reduced pathology and improved cognition in the 5XFAD mice. We propose that the partial antagonism of HK2, is effective in slowed disease progression and inflammation through a non-metabolic mechanism associated with the modulation of NFKβ signaling, through its cytosolic target IKBα. The complete loss of HK2 affects additional inflammatory mechanisms associated to mitochondrial dysfunction. Highlights Hexokinase 2, the first and rate-limiting enzyme of glycolysis, is specifically upregulated in plaque-associated microglia of AD mice models and in the postmortem cortex of human AD patients. Microglia haploinsufficient in HK2 exhibit reduced amyloid burden and inflammation as well as improved cognition in a mouse model of AD. Paradoxically, the complete loss of HK2 results in opposite effects, by exacerbating inflammation. Lonidamine, an anticancer drug that inhibits HK2, mimics the salutary effects of HK2 haploinsufficiency in the 5xFAD mice, but only in males during the early stages of disease. HK2 deletion induced mitochondrial dysfunction associated to increased expression of inflammasome elements and IL-1β. HK2 partial antagonism exerts beneficial effects independent of its energetic or mitochondrial role, likely through cytosolic stabilization of IκBα and inhibition of the NF-κB pathway, leading to reduced proinflammatory gene expression.

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