Aberrant Glycogen Modulates Cerebral Glucose Metabolism in Aging and Alzheimer's Disease

The onset of Alzheimer's disease increases in incidence with age, a rapidly aging demographic means the number of individuals suffering from AD is expanding precipitously. Current AD treatments only show incremental and temporary improvements in cognitive function, more significant advances in prognostic outcome for AD patients will likely depend on the identification of alternative disease target and treatment strategies. AD brains show clear metabolic impairments, studies suggest that altered metabolism drives the cascade of events leading to the onset of AD. The mechanism that initiate these metabolic impairments remain a critical knowledge gap in AD research. We recently discovered the aberrant glycogen accumulation in the hippocampal region of the AD patients (AD-glycogen). Increases in AD-glycogen correlated with higher Braak staging and lower glucose levels in patient specimens. AD-glycogen is both hyper-phosphorylated and hyper-branched making it architecturally distinct from normal glycogen. We present strong evidence showing that AD-glycogen modulates brain metabolism through direct binding and inactivation of the AMP-activated protein kinase (AMPK), a master regulator of central carbon metabolism. We will first elucidate the molecular events leading up to abnormal AD-glycogen formation in vitro and in vivo (Aim 1), then we will Interrogate the impact of AD-glycogen on cerebral metabolism (Aim 2). Finally, Assess the efficacy of a novel glycogen-clearing therapy on brain metabolism, cognition and AD neuropathology in vivo (Aim 3). The PI has assembled a multi- disciplinary team of investigators with complementary skillsets and state-of-art high resolution and Omic-based techniques to discover potential therapeutic options to prevent or delay the onset of AD.