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

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.