Project Summary Alzheimer’s Disease (AD) is an aging-associated disease defined by progressive neurodegeneration, neuroinflammation, and the presence of protein aggregates consisting of amyloid β (Aβ) and hyperphosphorylated tau. However, the molecular details of AD pathogenesis still need to be clarified. Interestingly, AD is associated with several neuronal abnormalities in energy metabolism such as mitochondrial dysfunctions and decline in glucose uptake, and defects in cholesterol metabolism and Ca2+ homeostasis. Our studies revealed that an energy sensor AMP-activated protein kinase (AMPK) regulates glucose transporter trafficking to modulate energy metabolism under both physiological and pathological conditions. We further identified a cytokine, macrophage migration inhibitory factor (MIF), which is one critical factor responsible for cardiac AMPK signaling regulation of energy metabolism in response to pathological stress. More epidemiological studies have reported that metabolic syndrome and cardiovascular diseases are risk factors for cognitive impairment and sporadic AD since metabolic disturbances and alterations in redox homeostasis increase the chances of cognitive decline and AD. AMPK signaling regulates pathways that control oxidative stress-related vascular inflammation and modulates tau protein phosphorylation and amyloidogenesis. We have found that an aging-related reduction in the MIF-AMPK signaling cascade is an important contributing factor leading to increased sensitivity to reactive oxygen species (ROS) from mitochondrial dysfunctions under pathological stress conditions. Considering the properties of MIF-AMPK signaling cascade in energy metabolism and inflammatory response, and age-related impaired AMPK signaling pathways in response to stress. We hypothesize that age-related AD is associated with a decline in the ability of the brain to render the MIF-AMPK signaling cascade active in response to aging caused pathological stress, thus resulting in exacerbated cerebral injury. We will test this hypothesis with the specific aim: define the role of the MIF receptor in age-related impaired AMPK signaling in response to pathological stress in AD and evaluate the capability of small-molecule MIF agonist to improve MIF-AMPK activation during AD pathogenesis. In this manner, we seek to advance our understanding of the mechanisms behind aging-related alterations in AMPK signaling pathways in response to alterations in metabolic homeostasis and neuroinflammation that occurred during AD pathogenesis.