| First Author | Son SM | Year | 2012 |
| Journal | Diabetes | Volume | 61 |
| Issue | 12 | Pages | 3126-38 |
| PubMed ID | 22829447 | Mgi Jnum | J:208510 |
| Mgi Id | MGI:5563629 | Doi | 10.2337/db11-1735 |
| Citation | Son SM, et al. (2012) Altered APP processing in insulin-resistant conditions is mediated by autophagosome accumulation via the inhibition of mammalian target of rapamycin pathway. Diabetes 61(12):3126-38 |
| abstractText | Insulin resistance, one of the major components of type 2 diabetes mellitus (T2DM), is a known risk factor for Alzheimer's disease (AD), which is characterized by an abnormal accumulation of intra- and extracellular amyloid beta peptide (Abeta). Insulin resistance is known to increase Abeta generation, but the underlying mechanism that links insulin resistance to increased Abeta generation is unknown. In this study, we examined the effect of high-fat diet-induced insulin resistance on amyloid precursor protein (APP) processing in mouse brains. We found that the induced insulin resistance promoted Abeta generation in the brain via altered insulin signal transduction, increased beta- and gamma-secretase activities, and accumulation of autophagosomes. These findings were confirmed in diabetic db/db mice brains. Furthermore, in vitro experiments in insulin-resistant SH-SY5Y cells and primary cortical neurons confirmed the alteration of APP processing by insulin resistance-induced autophagosome accumulation. Defects in insulin signal transduction affect autophagic flux by inhibiting the mammalian target of rapamycin pathway, resulting in altered APP processing in these cell culture systems. Thus, the insulin resistance that underlies the pathogenesis of T2DM might also trigger accumulation of autophagosomes, leading to increased Abeta generation, which might be involved in the pathogenesis of AD. |
