title: LINGO-1 promotes lysosomal degradation of amyloid-β protein precursor.
abstract: Sequential proteolytic cleavages of amyloid-β protein precursor (AβPP) by β-secretase and γ-secretase generate amyloid β (Aβ) peptides, which are thought to contribute to Alzheimer's disease (AD). Much of this processing occurs in endosomes following endocytosis of AβPP from the plasma membrane. However, this pathogenic mode of processing AβPP may occur in competition with lysosomal degradation of AβPP, a common fate of membrane proteins trafficking through the endosomal system. Following up on published reports that LINGO-1 binds and promotes the amyloidogenic processing of AβPP we have examined the consequences of LINGO-1/AβPP interactions. We report that LINGO-1 and its paralogs, LINGO-2 and LINGO-3, decrease processing of AβPP in the amyloidogenic pathway by promoting lysosomal degradation of AβPP. We also report that LINGO-1 levels are reduced in AD brain, representing a possible pathogenic mechanism stimulating the generation of Aβ peptides in AD.
authors.affiliation: Immusoft, Seattle, WA, USA.
authors.forename: Rian
authors.initials: R
authors.lastname: de Laat
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington and Mental Illness Research Education and Clinical Center, VA Medical Center, Seattle, WA, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Meabon
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Jesse C
authors.initials: JC
authors.lastname: Wiley
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Hudson
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA; mab@uw.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Bothwell
keywords: APP; Alzheimer's disease; AβPP proteolysis; LINGO; endosome; trafficking