Is Hexokinase 2 a Molecular Link Between TREM2 Signaling and Microglial Activity in Alzheimer Disease?

Alzheimer’s disease is a neurodegenerative disorder that induces the activation of the brain immune cells, the microglia. Mutations in a gene expressed only in microglia, TREM2, increase the risk of late-onset Alzheimer. However, the molecular mechanism involved in TREM2 function are not fully understood. In this study, we want to evaluate if TREM2 can induce metabolic changes in the microglia through the regulation of Hexokinase 2 an important enzyme of the metabolism of glucose.

This study aims to identify novel, effective therapeutic targets for AD. We propose to establish intervention targets in specific immunometabolism pathways that could slow or prevent AD progression by delineating the biology of interactions between TREM2, a master regulator of inflammation in the brain, and HK2, a key enzyme in cellular uptake and utilization of glucose. We hypothesize that HK2 is a critical regulator of the TREM2-induced microglial response during AD progression due to reciprocal regulation between glucose metabolism and immune responses. In our first aim we will investigate the molecular events that lead to HK2 expression following TREM2 activation. The expression and activation of HK2 regulators including transcription factors and signaling molecules will be analyzed in TREM2-deficient mice versus wild-type mice to identify the main molecular players. These will then be analyzed in vitro using loss-of-function and pharmacological assays to determine their effects on HK2 expression in response to amyloid-beta (Aβ). In our second aim we will determine the biological significance of HK2 expression in AD. We will generate a novel transgenic AD mouse model specifically lacking HK2 in adult mouse microglia to characterize the metabolic adaptations and immune responses of microglia in the absence of HK2 during AD progression. Identifying the key molecular players in AD provides a unique opportunity to tailor drugs to target specific cell populations while avoiding detrimental off-target effects on other populations. Several drugs targeting HK2 in cancer produced minimal side effects in clinical trials. If ours research aims are successful, we will evaluate the effects of these drugs in AD mouse models.