A Role of Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) in Astrocytic Aβ Clearance
Hongsheng Zhang, Wenbing Chen, Zhibing Tan, Lei Zhang, Zhaoqi Dong, Wanpeng Cui, Kai Zhao, Hongsheng Wang, Hongyang Jing, Rangjuan Cao, Chae Kim, Jiri Safar, Wen‐Cheng Xiong, Lin Mei
Abstract
Amyloid-b (Ab) deposition occurs years before cognitive symptoms appear and is considered a cause of Alzheimer's disease (AD). The imbalance of Ab production and clearance leads to Ab accumulation and Ab deposition. Increasing evidence indicates an important role of astrocytes, the most abundant cell type among glial cells in the brain, in Ab clearance. We explored the role of lowdensity lipoprotein receptor-related protein 4 (LRP4), a member of the LDLR family, in AD pathology. We show that Lrp4 is specifically expressed in astrocytes and its levels in astrocytes were higher than those of Ldlr and Lrp1, both of which have been implicated in Ab uptake. LRP4 was reduced in postmortem brain tissues of AD patients. Genetic deletion of the Lrp4 gene augmented Ab plaques in 5xFAD male mice, an AD mouse model, and exacerbated the deficits in neurotransmission, synchrony between the hippocampus and PFC, and cognition. Mechanistically, LRP4 promotes Ab uptake by astrocytes likely by interacting with ApoE. Together, our study demonstrates that astrocytic LRP4 plays an important role in Ab pathology and cognitive function.