Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Aβ42 uptake and lysosomal trafficking

Rodrigo A. Fuentealba, Qiang Liu, Juan Zhang, Takahisa Kanekiyo, Xiaoyan Hu, Jin Moo Lee, Mary Jo Ladu, Guojun D Bu

Research output: Contribution to journalArticle

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Abstract

Background: Alzheimer's disease (AD) is characterized by the presence of early intraneuronal deposits of amyloid-β 42 (Aβ42) 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 Aβ42 in the brain. Our previous findings suggest that the LDL receptor-related protein 1 (LRP1), a major receptor for apolipoprotein E, facilitates intraneuronal Aβ42 accumulation in mouse brain. However, direct evidence of neuronal endocytosis of Aβ42 through LRP1 is lacking. Methodology/Principal Findings: Here we show that LRP1 endocytic function is required for neuronal Aβ42 uptake. Overexpression of a functional LRP1 minireceptor, mLRP4, increases Aβ42 uptake and accumulation in neuronal lysosomes. Conversely, knockdown of LRP1 expression significantly decreases neuronal Aβ42 uptake. Disruptions of LRP1 endocytic function by either clathrin knockdown or by removal of its cytoplasmic tail decreased both uptake and accumulation of Aβ42 in neurons. Finally, we show that LRP1-mediated neuronal accumulation of Aβ42 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 Aβ42 in neuronal lysosomes. These findings emphasize the central function of LRP1 in neuronal Aβ metabolism.

Original languageEnglish (US)
Article numbere11884
JournalPLoS One
Volume5
Issue number7
DOIs
StatePublished - 2010
Externally publishedYes

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Low Density Lipoprotein Receptor-Related Protein-1
Lipoprotein Receptors
amyloid
low density lipoprotein
Amyloid
lipoproteins
uptake mechanisms
receptors
proteins
Proteins
Brain
Lysosomes
lysosomes
brain
Clathrin
clathrin
apolipoprotein E
Amyloid Plaques
Endocytosis
endocytosis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Aβ42 uptake and lysosomal trafficking. / Fuentealba, Rodrigo A.; Liu, Qiang; Zhang, Juan; Kanekiyo, Takahisa; Hu, Xiaoyan; Lee, Jin Moo; Ladu, Mary Jo; Bu, Guojun D.

In: PLoS One, Vol. 5, No. 7, e11884, 2010.

Research output: Contribution to journalArticle

Fuentealba, Rodrigo A. ; Liu, Qiang ; Zhang, Juan ; Kanekiyo, Takahisa ; Hu, Xiaoyan ; Lee, Jin Moo ; Ladu, Mary Jo ; Bu, Guojun D. / Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Aβ42 uptake and lysosomal trafficking. In: PLoS One. 2010 ; Vol. 5, No. 7.
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