| First Author | Liu CC | Year | 2017 |
| Journal | J Neurosci | Volume | 37 |
| Issue | 15 | Pages | 4023-4031 |
| PubMed ID | 28275161 | Mgi Jnum | J:240679 |
| Mgi Id | MGI:5888931 | Doi | 10.1523/JNEUROSCI.3442-16.2017 |
| Citation | Liu CC, et al. (2017) Astrocytic LRP1 Mediates Brain Abeta Clearance and Impacts Amyloid Deposition. J Neurosci 37(15):4023-4031 |
| abstractText | Accumulation and deposition of amyloid-beta (Abeta) in the brain represent an early and perhaps necessary step in the pathogenesis of Alzheimer's disease (AD). Abeta accumulation leads to the formation of Abeta aggregates, which may directly and indirectly lead to eventual neurodegeneration. While Abeta production is accelerated in many familial forms of early-onset AD, increasing evidence indicates that impaired clearance of Abeta is more evident in late-onset AD. To uncover the mechanisms underlying impaired Abeta 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 Abeta 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 Abeta clearance. LRP1 knockdown in primary astrocytes resulted in decreased cellular Abeta uptake and degradation. In addition, silencing of LRP1 in astrocytes led to downregulation of several major Abeta-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 Abeta clearance, exacerbated Abeta accumulation, and accelerated amyloid plaque deposition without affecting its production. Together, our results demonstrate that astrocytic LRP1 plays an important role in Abeta metabolism and that restoring LRP1 expression and function in the brain could be an effective strategy to facilitate Abeta clearance and counter amyloid pathology in AD.SIGNIFICANCE STATEMENT Astrocytes represent a major cell type regulating brain homeostasis; however, their roles in brain clearance of amyloid-beta (Abeta) and underlying mechanism are not clear. In this study, we used both cellular models and conditional knock-out mouse models to address the role of a critical Abeta receptor, the low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. We found that LRP1 in astrocytes plays a critical role in brain Abeta clearance by modulating several Abeta-degrading enzymes and cellular degradation pathways. Our results establish a critical role of astrocytic LRP1 in brain Abeta clearance and shed light on specific Abeta clearance pathways that may help to establish new targets for AD prevention and therapy. |
