Neuronal Clearance of Amyloid-β by Endocytic Receptor LRP1

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Accumulation, aggregation, and deposition of amyloid-beta (A beta) peptides generated through proteolytic cleavage of amyloid precursor protein (APP) are likely initiating events in the pathogenesis of AD. While A beta production is accelerated in familial AD, increasing evidence indicates that impaired clearance of A beta is responsible for late-onset AD. Because A beta is mainly generated in neurons, these cells are predicted to have the highest risk of encountering A beta among all cell types in the brain. However, it is still unclear whether they are also involved in A beta clearance. Here we show that receptor-mediated endocytosis in neurons by the low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in brain A beta clearance. LRP1 is known to be an endocytic receptor for multiple ligands including A beta. Conditional knock-out of Lrp1 in mouse forebrain neurons leads to increased brain A beta levels and exacerbated amyloid plaque deposition selectively in the cortex of amyloid model APP/PS1 mice without affecting A beta production. In vivo microdialysis studies demonstrated that A beta clearance in brain interstitial fluid is impaired in neuronal Lrp1 knock-out mice. Because the neuronal LRP1-deletion did not affect the mRNA levels of major A beta degrading enzymes, neprilysin and insulin-degrading enzyme, the disturbed A beta clearance is likely due to the suppression of LRP1-mediated neuronal A beta uptake and degradation. Together, our results demonstrate that LRP1 plays an important role in receptor-mediated clearance of A beta and indicate that neurons not only produce but also clear A beta.