37 RESULTS
COMMENT This paper in Cell Reports is a wake-up call for the field. It should revive interest in the γ-secretases, a field in Alzheimer’s research that got a severe blow some years ago when the failure of the semagacestat trial was announced (Doody et al., 2013). ...
COMMENT This failure was indeed predicted as a possible outcome of Aβ therapy (see Figure 4 of Karran et al., 2011). If Aβ is only a trigger then it will be really difficult to get the therapy right, because we do not understand when and how it triggers disease. ...
COMMENT The Brexit vote has shocked me, and from the reactions I hear at the Gordon Research Conference that I am attending, the Brexit is creating a lot of confusion and uncertainty among the British and to a lesser extent European scientific community. It is ...
COMMENT I hope that there are "clothes for this new emperor" (see Benilova et al., 2012). To the best of my knowledge, it remains a challenge to isolate a non-covalent oligomeric structure, as every technique may affect such assemblies. I very much look ...
COMMENT The paper of Chen and co-authors is highly interesting, supporting the concept that γ-secretases interact with α- and β-secretases and that the enzymes are clustered in specific subdomains in the cellular membranes. It remains to be sorted out to what ...
COMMENT I wonder whether the explanation that these antibodies bind partially with APP and APP CTF, which are heavily overexpressed in these mouse models, does not explain this finding. I would recommend expanding this study to include the knock-in mice from ...
COMMENT MicroRNA expression profiling studies of the AD brain have yielded invaluable information about microRNAs whose expression consistently differs between healthy and diseased CNS. These findings not only shed light on regulatory mechanisms possibly ...
COMMENT In 2007, I wrote: “From a genetic point of view, these mutations seem to result in a gain of toxic function; however, biochemically, they result in a partial loss of function in the γ-secretase complex, which affects several downstream signaling pathways. ...
COMMENT I would like to thank all contributors to the discussion for sharing really interesting thoughts. I also strongly appreciate the participation of industry and their constructive input. This type of interaction is very helpful and shows how far the field ...
COMMENT Glutamate excitotoxicity has been put forward as one of the mechanisms at play in Alzheimer’s disease and other neurodegenerative conditions. In this paper, Verma et al. describe a very interesting microRNA-mediated mechanism for fine-tuning glutamatergic ...
COMMENT BACE1 stands as a very attractive therapeutic target for AD. However, with the identification of physiologically relevant BACE1 substrates, one should be aware that a complete block of BACE1 activity may lead to unintended side effects similar to what was ...
COMMENT This study of the Tomita and Iwatsubo laboratories is exciting. It provides via a whole series of cleverly designed and carefully executed experiments a first glimpse into the mechanism of the γ-secretase modulators (GSM). The paper identifies several ...
COMMENT Regarding the question of how presenilin FAD mutations affect Aβ production that is being debated here, current research suggests a complex answer. In brief, mutations causing FAD affect γ-secretase processing at three levels to different extents. The ...
COMMENT Nussbaum et al. show that when as little as 5 percent of Aβ is in the pyroglutamylated N-truncated form (Aβ 3(pE)-42), it confers toxicity to a solution of Aβ1-42 monomers. The authors suggest that Aβ42 undergoes prion-like templated conversion induced by ...
COMMENT We read with great interest the manuscript of Zhang et al. They provide preliminary evidence for a predicted novel peptide-binding region in the ectodomain of nicastrin (Nct), which could have a potential role in substrate recruitment to the γ-secretase ...
