An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimerís disease

(Note: With the exception of the correction of typographical or spelling errors that could be a source of ambiguity, letters and reports are not edited. The original formatting of letters and referee reports may not be reflected in this compilation.) Thank you for the submission of your manuscript to EMBO Molecular Medicine. In this case we experienced unusual difficulties in securing three willing and appropriate reviewers. As a further delay cannot be justified I have decided to proceed based on the two available consistent evaluations. Both Reviewers find merits in your manuscript although they raise significant issues that require your action. I will not dwell into much detail as their comments are detailed. I would like, however, to highlight a few main points. Reviewer 1, as you will see, has two orders of concerns. On one hand s/he notes that the findings described in this manuscript are in stark contrast with previous work and suggests a number of avenues to directly address this issue. On the other hand, the Reviewer notes inadequate experimental support for some of the claims. One important example is that the Mgat3 GOF/LOF experiments should be performed in neurons. I should mention here that Reviewer 2 has exactly the same concern. Another important caveat, and I agree, is that to correctly assess the clinical relevance of your findings, it would be important to assess the consequences of BACE1 modification also on substrates other than APP. Finally, this Reviewer also mentions that the effects of Mgat3 deficiency should be assessed on an alternative mouse setting to ascertain whether the effects are model specific. This Reviewer lists many other action points for your consideration.