Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Mediates Neuronal Aβ42 Uptake and Lysosomal Trafficking

Background: Alzheimer's disease (AD) is characterized by the presence of early intraneuronal deposits of amyloid-beta 42 (A beta 42) that precede extracellular amyloid deposition in vulnerable brain regions. It has been hypothesized that endosomal/lysosomal dysfunction might be associated with the pathological accumulation of intracellular A beta 42 in the brain. Our previous findings suggest that the LDL receptor-related protein 1 (LRP1), a major receptor for apolipoprotein E, facilitates intraneuronal A beta 42 accumulation in mouse brain. However, direct evidence of neuronal endocytosis of A beta 42 through LRP1 is lacking. Methodology/Principal Findings: Here we show that LRP1 endocytic function is required for neuronal A beta 42 uptake. Overexpression of a functional LRP1 minireceptor, mLRP4, increases A beta 42 uptake and accumulation in neuronal lysosomes. Conversely, knockdown of LRP1 expression significantly decreases neuronal A beta 42 uptake. Disruptions of LRP1 endocytic function by either clathrin knockdown or by removal of its cytoplasmic tail decreased both uptake and accumulation of A beta 42 in neurons. Finally, we show that LRP1-mediated neuronal accumulation of A beta 42 is associated with increased cellular toxicity. Conclusions/Significance: These results demonstrate that LRP1 endocytic function plays an important role in the uptake and accumulation of A beta 42 in neuronal lysosomes. These findings emphasize the central function of LRP1 in neuronal A beta metabolism.