LINGO-1 promotes lysosomal degradation of amyloid-β protein precursor.

Sequential proteolytic cleavages of amyloid-b protein precursor (AbPP) by b-secretase and g-secretase generate amyloid b (Ab) peptides, which are thought to contribute to Alzheimer's disease (AD). Much of this processing occurs in endosomes following endocytosis of AbPP from the plasma membrane. However, this pathogenic mode of processing AbPP may occur in competition with lysosomal degradation of AbPP, 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 AbPP we have examined the consequences of LINGO-1/AbPP interactions. We report that LINGO-1 and its paralogs, LINGO-2 and LINGO-3, decrease processing of AbPP in the amyloidogenic pathway by promoting lysosomal degradation of AbPP. We also report that LINGO-1 levels are reduced in AD brain, representing a possible pathogenic mechanism stimulating the generation of Ab peptides in AD.