Interconnections of insulin/IGF‐1 signaling and autophagy abnormalities in Alzheimer's disease

Abstract INTRODUCTION Impaired insulin (INS) and insulin‐like growth factor 1 (IGF‐1) signaling are features of both brain aging and late‐onset Alzheimer's disease (LOAD). However, their exact underlying mechanisms and cause‐and‐effect linkages, including the downstream regulation of endocytosis and autophagy, are still not well understood. METHODS We investigated INS/IGF‐1 signaling and its connection with endocytic and autophagic processes in fibroblasts from LOAD patients and healthy young or old control individuals. RESULTS Compared to control old‐age cells, protein levels in the INS/IGF‐1 signaling cascade were elevated in LOAD cells, but activation of AKT was reduced. The activation of the INS/IGF‐1/AKT/FOXO1 or mTOR axes and associated endo‐ and autophagic processes were largely intact in old‐age but disrupted in LOAD fibroblasts. DISCUSSION Our results suggest that reduced AKT activation, in the context of altered INS/IGF‐1 signaling, and connected alterations of endocytosis and autophagy are features of LOAD pathology but not aging, per se. Highlights Levels of insulin/insulin‐like growth factor 1 (INS/IGF‐1) factors in late‐onset Alzheimer's disease (LOAD) cells are higher than in healthy old controls. AKT activation by INS/IGF‐1 signaling is specifically diminished in LOAD cells. INS/IGF‐1/AKT/forkhead box protein O1/mechanistic target of rapamycin kinase related endocytosis/autophagy are disrupted in LOAD cells. Intracellular endocytic/autophagic structure distribution is altered in LOAD cells. INS/IGF‐1 reverses endocytic/autophagic processes in LOAD versus old control cells.