LAUSR

Pathogenesis of Alzheimer's disease (AD) affects not only central nervous system, but also peripheral glucose and lipid metabolism. We recently find the hepatic mitochondrial metabolic remodeling arises at the early stage of AD. For example, we have demonstrated that early inflammation-associated factors diminish high fat diet-induced hepatic lipid deposition by inhibiting SREBP-1-mediated de novo lipogenesis in APP/PS1 mice, thus driving substrate flux to glucose production for hyperglycemia and hepatic insulin resistance. We also reveal that hepatic inflammatory factor enhances ketogenesis (hydroxybutyrate) through HMGCS2 (3-hydroxy-3- methylglutaryl-CoA synthase 2) signaling activation by p38/NF-kappa B p65. These results provide a novel peripheral metabolic remodeling and suggest a plausible early AD phenotype to diagnose AD. More importantly, we define a group of compounds targeting mitochondria and benefiting mitochondrial metabolic function as “mitochondrial nutrients”, promising agents in AD prevention and treatment.