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

Jacob M. Basak, Philip B. Verghese, Hyejin Yoon, Jungsu Kim, David M. Holtzman

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)13959-13971
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number17
DOIs
StatePublished - Apr 20 2012
Externally publishedYes

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LDL Receptors
Apolipoproteins E
Astrocytes
Degradation
Brain
Neuroglia
Cell Surface Receptors
Lysosomes
Amyloid
Alzheimer Disease

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Aβ uptake and degradation by astrocytes. / Basak, Jacob M.; Verghese, Philip B.; Yoon, Hyejin; Kim, Jungsu; Holtzman, David M.

In: Journal of Biological Chemistry, Vol. 287, No. 17, 20.04.2012, p. 13959-13971.

Research output: Contribution to journalArticle

Basak, Jacob M. ; Verghese, Philip B. ; Yoon, Hyejin ; Kim, Jungsu ; Holtzman, David M. / Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Aβ uptake and degradation by astrocytes. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 17. pp. 13959-13971.
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