Rapid endocytosis of the low density lipoprotein receptor-related protein modulates cell surface distribution and processing of the β-amyloid precursor protein

Judy A. Cam, Celina V. Zerbinatti, Yonghe Li, Guojun D Bu

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

The low density lipoprotein receptor-related protein (LRP) is a ∼600-kDa multifunctional endocytic receptor that is highly expressed in the brain. LRP and its ligands apolipoprotein E, α2-macroglobulin, and β-amyloid precursor protein (APP), are genetically linked to Alzheimer disease and are found in characteristic plaque deposits in brains of patients with Alzheimer disease. To identify which extracellular domains of LRP interact with APP, we used minireceptors of each of the individual LRP ligand binding domains and assessed their ability to bind and degrade a soluble APP fragment. LRP minireceptors containing ligand binding domains II and IV, but not I or III, interacted with APP. To test whether APP trafficking is directly related to the rapid endocytosis of LRP, we generated stable Chinese hamster ovary cell lines expressing either a wild-type LRP minireceptor or its endocytosis mutants. Chinese hamster ovary cells stably expressing wild-type LRP minireceptor had less cell surface APP than pcDNA3 vector-transfected cells, whereas those stably expressing endocytosis-defective LRP minireceptors accumulated APP at the cell surface. We also found that the steady-state levels of the amyloid β-peptides (Aβ) is dictated by the relative expression levels of APP and LRP, probably reflecting the dual roles of LRP in both Aβ production and clearance. Together, these data establish a relationship between LRP rapid endocytosis and APP trafficking and proteolytic processing to generate Aβ.

Original languageEnglish (US)
Pages (from-to)15464-15470
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number15
DOIs
StatePublished - Apr 15 2005
Externally publishedYes

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LDL-Receptor Related Proteins
Lipoprotein Receptors
Amyloid beta-Protein Precursor
LDL Receptors
Endocytosis
Membrane Proteins
Processing
Proteins
Amyloid
Protein Transport
Ligands
Cricetulus
Ovary
Alzheimer Disease
Brain
Apolipoprotein E2
Cells
Macroglobulins
Aptitude
Protein Binding

ASJC Scopus subject areas

  • Biochemistry

Cite this

Rapid endocytosis of the low density lipoprotein receptor-related protein modulates cell surface distribution and processing of the β-amyloid precursor protein. / Cam, Judy A.; Zerbinatti, Celina V.; Li, Yonghe; Bu, Guojun D.

In: Journal of Biological Chemistry, Vol. 280, No. 15, 15.04.2005, p. 15464-15470.

Research output: Contribution to journalArticle

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