Down-regulating insulin-like growth factor-1 receptor reduces amyloid-ß deposition in mice cortex induced by chronic sleep restriction.

ABSTRACT

OBJECTIVE: Insufficient sleep affects cognitive function, but the underlying mechanism and potential protective ways are yet to be fully understood. This study aimed to explore the influence of chronic sleep restriction (CSR) on the insulin-like growth factor-1 (IGF-1) signaling pathway, and whether down-regulating IGF-1 signaling pathway would modulate amyloid-ß (Aß) peptides metabolism and its cortical deposition after CSR. Methods 8-week IGF-1R+/- mice and wild-type (WT) C57BL/6 (C57) mice were divided into four groups IGF-1R+/- CSR (MUSR), IGF-1R+/- control (MUCO), C57 CSR (C57SR) and C57 control (C57CO). CSR model was established by application of slowly rotating drum for 2 months. Body weight and Lee's index were measured. The level of IGF-1 in plasma was measured by enzyme linked immunosorbent assay (ELISA). Aß accumulation was detected by immunofluorescence. The expressions of amyloid precursor protein (APP), ß-site amyloid precursor protein-cleaving enzyme-1 (BACE-1) and C99 were detected using western-blot (WB). Results Two-way ANOVA showed genotypic effect was significant on body weight and Lee's index. Neither treatment effect nor interaction reached significant difference on body weight and Lee's index. The level of IGF-1 in plasma was significantly decreased in C57SR compared with C57CO. Besides, compared with C57CO, Aß was markedly accumulated in frontal cortex, in parallel with increased expressions of BACE-1 and C99, and with no difference of APP in C57SR group. Further, no significant changes of Aß, BACE-1, C99 and APP were detected in MUSR compared with MUCO. Conclusions This study showed that CSR could induce the decrease of circulating IGF-1 in mice. By using the IGF-1R+/- mice, we found that down-regulating IGF-1R could reduce Aß deposition in mice frontal cortex after CSR via inhibiting BACE-1 protein expression and activity, which were independent of the changes of body weight and Lee's index. These findings indicate that the blockage of IGF-1 signaling pathway might be a protection mechanism for alleviating the impact of CSR.