A Role of Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) in Astrocytic Aβ Clearance

Amyloid-beta (A beta) deposition occurs years before cognitive symptoms appear and is considered a cause of Alzheimer's disease (AD). The imbalance of A beta production and clearance leads to A beta accumulation and A beta deposition. Increasing evidence indicates an important role of astrocytes, the most abundant cell type among glial cells in the brain, in A beta clearance. We explored the role of low-density 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 Aft uptake. LRP4 was reduced in postmortem brain tissues of AD patients. Genetic deletion of the Lrp4 gene augmented A beta 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 A beta uptake by astrocytes likely by interacting with ApoE. Together, our study demonstrates that astrocytic LRP4 plays an important role in A beta pathology and cognitive function.