Insulin-like growth factor-1 enhances β-amyloid protein clearance in HMC3 microglia via low-density lipoprotein receptor-related protein 1-mediated pathway.

β-amyloid protein (Aβ) deposition occurs years before cognitive symptoms appear and is considered one of the main causes underlying the pathogenic events that occur in Alzheimer's disease (AD). Mounting evidence suggests that the imbalance of Aβ production and clearance leads to the accumulation of Aβ and the subsequent formation of toxic Aβ aggregates. Aβ is internalized by microglia and transported to lysosomes for degradation, which is one of the main ways by which Aβ may be cleared from the brain. Insulin-like growth factor-1 (IGF-1) promotes clearance of Aβ in the brain by enhancing Aβ carrier proteins. Our previous study demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1) mediates the internalization of Aβ1-42 and lysosomal trafficking in primary cortical neurons. However, whether IGF-1 enhances the clearance of Aβ in microglia through the LRP1-mediated pathway and its underlying mechanisms is incompletely understood. Here, we reported that knockdown of LRP1 expression significantly decreased the internalization of Aβ1-42 in HMC3 cells. Furthermore, pretreatment with IGF-1 significantly increased intracellular Aβ1-42, indicating IGF-1 enhances HMC3 cells uptake of extracellular Aβ1-42. Interestingly, the intracellular Aβ1-42 in LRP1-knockdown HMC3 cells was reduced after preincubation with IGF-1. Thus, it was indicated that LRP1 is essential for IGF-1-enhanced internalization of Aβ1-42 in HMC3 cells. Moreover, IGF-1 significantly inhibited the downregulation of PI3K, phospho-PI3K, Akt, and phospho-Akt induced by Aβ1-42. Importantly, treatment with LY294002, a PI3K inhibitor, significantly reduced the intracellular Aβ1-42 levels and decreased the expression of LRP1. These findings indicated that IGF-1 enhances the internalization of Aβ in a LRP1-dependent manner by activating the PI3K/Akt signaling pathway. Finally, we identified that IGF-1 promotes lysosomal proteolysis of Aβ1-42 by increasing cathepsin B (CTSB) and cathepsin D (CTSD) expression. Consequently, these results demonstrated that IGF-1 promotes the internalization and lysosomal degradation of Aβ by microglia, which is an effective approach to lowering brain Aβ levels, and it might be a promising therapeutic target for AD.