| Proteolytic cleavage of amyloid precursor protein (APP) generates the amyloid beta peptide (Abeta), the main component of cortical and subcortical plaques in Alzheimer's disease (AD). APP can be processed at the cell surface or within endosomes after endocytosis, and via an amyloidogenic or non-amyloidogenic pathway. Along the amyloidogenic pathway, APP is first cleaved by beta-secretase followed by gamma-secretase to produce Abeta. The non-amyloidogenic pathway involves cleavage by alpha-secretase and then gamma-secretase. Abeta generation is thought to occur in a variety of organelles where APP, beta- and gamma-secretase reside. Proteins that regulate endocytosis and trafficking can thus control the qualitative proteolysis of APP, and consequently may be associated with pathophysiology of AD. One such protein is Lingo-1, which promotes APP trafficking to the lysosome and concomitant degradation, independent of the secretory pathway. In this manner, Lingo-1 may function as a control mechanism for APP levels. |
