Alzheimer?s disease (AD) is typified by amyloid deposition in the brain, which provokes a robust microglial mediated inflammatory response. Gene expression analysis of microglia in AD mouse models and patients has revealed acquisition of a disease related gene expression signature that accompanies the morphological and phenotypic changes exhibited by microglia associated with A?-plaques. It has only recently been appreciated that the plaque associated microglia undergo a fundamental reprogramming of cellular metabolism necessary to power the manifold phenotypic changes and cellular activities. Homeostatic microglia rely on mitochondrial oxidative metabolism to generate ATP necessary for normal housekeeping. However, the plaque associated microglia rapidly shift their metabolism from oxidative phosphorylation to aerobic glycolysis, which results in the rapid (10-100 fold faster) generation of ATP necessary to power the microglia migration, proliferation, phagocytosis and the envelopment of amyloid plaques exhibited by these cells. Increases in glycolysis are widely acknowledged to be a hallmark of pro-inflammatory immune cell activation. The initial and rate limiting enzyme in glycolysis is hexokinase, however, in the brain only hexokinase 2 (HK2) is expressed in microglia and are the only cell type in the brain to express this isoform. HK2 expression is directly correlated with the rate of glycolysis and is induced in response to metabolic demand and subject to sophisticated regulation. HK2 plays critical roles in inflammation through its actions in driving glycolysis, mediating the rapid production of ATP necessary to power the immune response. We report that in the AD brain there is a significant increase in the levels of HK2 selectively within plaque associated microglia and its expression is dependent upon TREM2. We hypothesize that HK2 antagonism will act to sustain expression of the microglial homeostatic phenotype, and prevent the transition to a neurodegenerative phenotype, attenuating disease progression. A primary goal of these studies is to establish whether metabolic intervention strategies attenuate disease pathogenesis.
The specific aims are:
Aim 1. Mechanisms of microglial regulation of HK2 expression and induction of glycolysis. We will establish the signaling pathways in microglia that regulate the expression of HK2 and the induction of glycolysis and the mechanisms through which TREM2 influences HK2 Aim 2 Conditional Inactivation of microglial HK2 in a murine model of AD We will selectively and inducibly inactivate HK2 expression in microglia in the 5XFAD model of AD and evaluate if inhibition of HK2-dependent glycolysis affects AD pathogenesis and cognitive function.
Aim 3. Evaluation of the therapeutic utility of a pharmacological inhibitor of HK2 in 5XFAD mice. We will evaluate the efficacy of the hexokinase inhibitor, lonidamine (LND) on disease progression and behavior.
Alzheimer?s disease (AD) is the most common cause of dementia, and the biological processes subserving the disease are not understood. We will investigate how the disease alters energy metabolism necessary for the immune response that exacerbates disease progression. These studies will inform the development of new therapeutics targeting immune cells in the AD brain.
