It is great to see the continuation of the work on sorLA. The authors previously found that this protein influences APP shedding and Aβ generation, both under overexpression and knockout conditions. Their new work sheds more light on the underlying molecular mechanisms. In contrast to many soluble, cytoplasmic proteins that can bind APP and alter APP shedding, sorLA is one of very few membrane proteins that have been reported to coimmunoprecipitate with APP. The authors propose that sorLA interferes with complex formation between APP and BACE1. It will be interesting to see how exactly sorLA interacts with APP/C99 and BACE1, and whether the interaction is mediated through the transmembrane domains or through the cytoplasmic domains. Potentially, sorLA may also interact with the other APP secretases, in particular with the ADAM proteases.

View all comments by Stefan Lichtenthaler

This is the latest paper in a series of studies looking at the modifying effect of LR11/SorLA on APP processing. Despite some differences to the previous paper by Andersen and coworkers, this study clearly highlights that increases in LR11/SorLA expression reduce Aβ generation. In further studies, it will be interesting to learn more about the underlying molecular mechanisms and the suitability of LR11 as a drug target.

View all comments by Stefan Lichtenthaler