35 RESULTS
COMMENT This study provides exciting mechanistic insights into how APP CTFs, and not Aβ, may contribute to the lysosomal dysfunction in Alzheimer’s disease. This cell biological study is comprehensive, carefully conducted, convincing, and in good agreement with p
COMMENT This is an exciting study implicating the BACE1-generated APP C-terminal fragment as a key player in lysosomal dysfunction in Down’s syndrome fibroblasts and animal models. This work has a major translational implication for the use of BACE inhibitors. Th
COMMENT This study reports a very important finding for Alzheimer's disease and specifically for the development of BACE1-targeted inhibitors. The study demonstrates that the protective Icelandic mutation—located close to the BACE1 cleavage site in APP—lower
COMMENT The new GF knock-in mouse line is a very welcome addition to the toolbox of AD mouse models. Similar to previously generated models from the same group or by Denali, it expresses APP at endogenous levels but avoids the widely used Swedish mutation, which
COMMENT This paper raises the exciting possibility of a second life for BACE inhibitors in glioblastoma treatment. Additionally, the paper suggests that BACE1 may have more substrates/functions than anticipated, and that they may not be restricted to neurons, whe
COMMENT This new mouse model is a very welcome addition to the toolbox of AD mouse models. It avoids the Arctic mutation, which is helpful for some questions, but not necessarily for others. It is great that the authors will make their mouse model easily availabl
COMMENT The finding that elenbecestat largely avoided the cognitive worsening seen in studies with other BACE inhibitors is very encouraging. I take this as clear evidence that BACE1 inhibition can be achieved in a safe manner. In hindsight it appears that the st
COMMENT I congratulate both companies on sharing more detailed data from the terminated trials and on their collaborative effort to compare two trials and inhibitors. This is very important to better understand the effects, but also the side effects, of BACE inhi
COMMENT This is a highly interesting and technically well-controlled study, convincingly demonstrating how GGA3-mediated changes in BACE1 trafficking lead to axonal damage, which also happens early in AD pathogenesis. This new study is the latest in a series from
COMMENT This paper is a technical tour de force and elegantly demonstrates the relevance of BACE2 as an anti-amyloidogenic protease, at least in trisomy 21 cerebral organoids. It also opens the exciting possibility that SNPs in BACE2 may control the age of onset
COMMENT This is very disappointing news—both for the patients and for drug development using BACE1 as a drug target. A major question that arises from the stopped elenbecestat trials is: What is the nature of the side effects observed? Is it an off-target effect,
COMMENT This is sad news—both for the patients and for drug discovery using BACE1 as a drug target. A major question that arises from the stopped CNP-520 trials is: What is the mechanistic cause of the cognitive decline observed for a few different BACE1-targeted
COMMENT This is a compelling story with in vitro and in vivo experiments describing a new cellular pathway controlling BACE1 expression, activity, and amyloid pathology. Excitingly, they even found that a pharmacological activation of this pathway may be exploite
COMMENT This is an elegant follow-up of the authors’ previous paper on the interaction between α- and γ-secretase. This is an important study with a very interesting concept, in that β-secretase forms a complex with γ-secretase, which may allow easy proteolytic p
COMMENT This excellent and carefully conducted study finally demonstrates that most of the phenotypes observed so far in BACE1-deficient mice are of developmental origin and may not be a cause of concern for the BACE inhibitors tested in the clinic. Yet, the auth
