Low-density Lipoprotein Receptor Represents an Apolipoprotein E-independent Pathway of Aβ Uptake and Degradation by Astrocytes

Accumulation of the amyloid beta (A beta) peptide within the brain is hypothesized to be one of the main causes underlying the pathogenic events that occur in Alzheimer disease (AD). Consequently, identifying pathways by which A beta is cleared from the brain is crucial for better understanding of the disease pathogenesis and developing novel therapeutics. Cellular uptake and degradation by glial cells is one means by which A beta may be cleared from the brain. In the current study, we demonstrate that modulating levels of the low-density lipoprotein receptor (LDLR), a cell surface receptor that regulates the amount of apolipoprotein E (apoE) in the brain, altered both the uptake and degradation of A beta by astrocytes. Deletion of LDLR caused a decrease in A beta uptake, whereas increasing LDLR levels significantly enhanced both the uptake and clearance of A beta. Increasing LDLR levels also enhanced the cellular degradation of A beta and facilitated the vesicular transport of A beta to lysosomes. Despite the fact that LDLR regulated the uptake of apoE by astrocytes, we found that the effect of LDLR on A beta uptake and clearance occurred in the absence of apoE. Finally, we provide evidence that A beta can directly bind to LDLR, suggesting that an interaction between LDLR and A beta could be responsible for LDLR- mediated A beta uptake. Therefore, these results identify LDLR as a receptor that mediates A beta uptake and clearance by astrocytes, and provide evidence that increasing glial LDLR levels may promote A beta degradation within the brain.