6562 Understanding The Role Of The Novel Hexokinase HKDC1 In Alzheimer’s Disease

Abstract Disclosure: Z. Farooq: None. B.T. Layden: None. Alzheimer’s disease (AD) is a chronic neurodegenerative condition, clinically characterized by loss of neurons. AD is responsible for causing 70% of global cases of dementia and constitutes and huge health and socio-economic burden, with limited availability of therapeutic options. While loss of neuronal integrity in AD is known, studies thus far have focused only on the deposition of amyloid plaques, leaving a huge gap in our understanding of the role of metabolic regulation and inflammation associated with AD. Studies in the literature suggest a link between accumulation of amyloid beta plaques, altered insulin action, and perturbed hypothalamic glucoregulation in AD pathology leading to increased hepatic glucose production and hyperglycemia. However, the complex mechanisms underlying the deleterious impact of metabolic derangements and insulin resistance on AD pathogenesis are poorly characterized. HKDC1, the fifth hexokinase, is highly expressed in the normal brain, with decline in expression observed in aging and Alzheimer’s disease mice models, but its function remains entirely unexplored. However, it is known to be involved in gestational diabetes mellitus (GDM), type 2 diabetes (T2D), and fatty liver disease. In this study, we explored the role of brain specific HKDC1 in pathogenesis of AD with our brain specific HKDC1 knock out (KO) and other mice models. We have observed that loss of HKDC1 in the brain is accompanied by dysregulation of glucose metabolism, decline in memory and learning, and an increase in senescence and neuroinflammation in mice. Interestingly, we have also observed that HKDC1 is exclusively localized to mitochondria in the brain and its absence leads to a reduction in the expression of markers of mitochondrial biogenesis, while causing an increase in tau-phosphorylation and ER stress. Through RNA sequencing, we have also identified novel targets of HKDC1 in the brain related to metabolic networks, triggering the pathogenesis of AD downstream of HKDC1. These findings uncover a novel role for HKDC1 as a key metabolic gene involved in the pathogenesis of AD in a mitochondrial-dependent manner in mice. Further studies on dissecting the molecular mechanism of HKDC1 involvement in AD could define a novel strategy for timely intervention of Alzheimer’s disease and possibly other forms of dementia. Presentation: 6/1/2024