Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition

Accumulation and deposition of amyloid-beta (A beta) in the brain represent an early and perhaps necessary step in the pathogenesis of Alzheimer's disease (AD). A beta accumulation leads to the formation of A beta aggregates, which may directly and indirectly lead to eventual neurodegeneration. While A beta production is accelerated in many familial forms of early-onset AD, increasing evidence indicates that impaired clearance of A beta is more evident in late-onset AD. To uncover the mechanisms underlying impaired A beta clearance in AD, we examined the role of low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. Although LRP1 has been shown to play critical roles in brain A beta metabolism in neurons and vascular mural cells, its role in astrocytes, the most abundant cell type in the brain responsible for maintaining neuronal homeostasis, remains unclear. Here, we show that astrocytic LRP1 plays a critical role in brain A beta clearance. LRP1 knockdown in primary astrocytes resulted in decreased cellular A beta uptake and degradation. In addition, silencing of LRP1 in astrocytes led to downregulation of several major A beta-degrading enzymes, including matrix metalloproteases MMP2, MMP9, and insulin-degrading enzyme. More important, conditional knock-out of the Lrp1 gene in astrocytes in the background of APP/PS1 mice impaired brain A beta clearance, exacerbated A beta accumulation, and accelerated amyloid plaque deposition without affecting its production. Together, our results demonstrate that astrocytic LRP1 plays an important role in A beta metabolism and that restoring LRP1 expression and function in the brain could be an effective strategy to facilitate A beta clearance and counter amyloid pathology in AD.