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Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of A? uptake and degradation by astrocytes.


ABSTRACT: Accumulation of the amyloid ? (A?) 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? 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? 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? by astrocytes. Deletion of LDLR caused a decrease in A? uptake, whereas increasing LDLR levels significantly enhanced both the uptake and clearance of A?. Increasing LDLR levels also enhanced the cellular degradation of A? and facilitated the vesicular transport of A? to lysosomes. Despite the fact that LDLR regulated the uptake of apoE by astrocytes, we found that the effect of LDLR on A? uptake and clearance occurred in the absence of apoE. Finally, we provide evidence that A? can directly bind to LDLR, suggesting that an interaction between LDLR and A? could be responsible for LDLR-mediated A? uptake. Therefore, these results identify LDLR as a receptor that mediates A? uptake and clearance by astrocytes, and provide evidence that increasing glial LDLR levels may promote A? degradation within the brain.

SUBMITTER: Basak JM 

PROVIDER: S-EPMC3340151 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Aβ uptake and degradation by astrocytes.

Basak Jacob M JM   Verghese Philip B PB   Yoon Hyejin H   Kim Jungsu J   Holtzman David M DM  

The Journal of biological chemistry 20120301 17


Accumulation of the amyloid β (Aβ) 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 Aβ 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 Aβ may be cleared from the brain. In the current study, we demonstrate that modulat  ...[more]

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