The p38 mitogen-activated protein kinase signaling pathway is involved in regulating low-density lipoprotein receptor-related protein 1-mediated beta-amyloid protein internalization in mouse brain

摘要

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Recently, increasing evidence suggests that intracellular beta-amyloid protein (A beta) alone plays a pivotal role in the progression of AD. Therefore, understanding the signaling pathway and proteins that control A beta internalization may provide new insight for regulating A beta levels. In the present study, the regulation of A beta internalization by p38 mitogen-activated protein kinases (MAPK) through low-density lipoprotein receptor-related protein 1 (LRP1) was analyzed in vivo. The data derived from this investigation revealed that A beta(1-42) were internalized by neurons and astrocytes in mouse brain, and were largely deposited in mitochondria and lysosomes, with some also being found in the endoplasmic reticulum. A beta(1-42)-LRP1 complex was formed during A beta(1-42) internalization, and the p38 MAPK signaling pathway was activated by A beta(1-42) via LRP1. A beta(1-42) and LRP1 were co-localized in the cells of parietal cortex and hippocampus. Furthermore, the level of LRP1-mRNA and LRP1 protein involved in A beta(1-42) internalization in mouse brain. The results of this investigation demonstrated that A beta(1-42) induced an LRP1-dependent pathway that related to the activation of p38 MAPK resulting in internalization of A beta(1-42). These results provide evidence supporting a key role for the p38 MAPK signaling pathway which is involved in the regulation of A beta(1-42) internalization in the parietal cortex and hippocampus of mouse through LRP1 in vivo. (C) 2016 Elsevier Ltd. All rights reserved.