11527 RESULTS
COMMENT This publication builds on Silke Nuber’s work on sex differences in PD in vivo models (Rajsombath et al., 2019), and that of Dennis Selkoe and Gary Ho on palmitoylation modifying αS PD phenotypes including neurotoxicity and αS accumulation (Ho et al., 202
COMMENT Underlying causes of sex differences in PD susceptibility is something of a black box, and these studies are headed in the right direction. The experiments are technically excellent, and the data are very clear. More studies focused on this important prob
COMMENT Bilousova, University of California, San Francisco, is the co-author of this comment. karen.gylys_373866
COMMENT While it is encouraging to see alternative hypotheses being generated from post hoc data analyses, I'm not certain the field has fully come to grips with the lack of correlation between amount of amyloid removal and clinical efficacy. This is certain
COMMENT The 2017 Nature paper by the Holtzman group describing their findings that ApoE accelerates Tau pathology (Shi et al., 2017), even in the absence of amyloid pathology (van der Kant et al., 2020), has been a major conceptual breakthrough in understanding t
COMMENT As a note of historical clarification, while not mentioned in this article, the first second-generation, non-NSAID, GSMs were discovered by Steve Wagner and me in 2002 at Neurogenetics, Inc., later TorreyPines Therapeutics, Inc. Our original GSM program w
COMMENT De Strooper and colleagues examined the function of γ-secretase in microglia using both cellular and mouse models and offer exciting insights into γ-secretase’s action in microglia in response to amyloid insult. γ-Secretase-mediated signal pathways play i
COMMENT The new study by Hou and coworkers in the lab of Bart de Strooper describes an interesting system-biology-based proteomics approach to unravel membrane substrates used by γ-secretase in cultured microglia cells. They found that at least 85 microglial memb
COMMENT In the past, analysis of γ-secretase (GS) substrates has been hampered by technical limitations. In this study, Hou et al. designed a very clever way of identifying novel substrates in an unbiased way. The failure of GSIs in the clinic was attributed in p
COMMENT We checked to what extent the 85 γ-secretase substrates described in figure 2b of this paper were associated with distinct Alzheimer’s disease molecular subtypes we identified (Tijms et al., 202 3). These AD subtypes were defined based on untargeted CSF p
COMMENT This paper represents impressive work. Hou et al performed a series of intriguing experiments, focusing on the potential substrate map of one of the most promiscuous enzymes–γ-secretase–and on its role in microglial activation. First, they conducted mass
COMMENT Here, I respectfully avoid commenting on data as those papers are in the preprint stage. On the
COMMENT My remarks below are in reply to Lucia Chávez-Gutiérrez's comments on Devkota et al. The term
COMMENT Since we now know that Aβ-immunotherapies work, I think the next step is also to have small molecules against Aβ generation, for example to eventually be used in maintenance therapies after immunotherapy. One could also think of prevention therapies with
COMMENT Gamma-secretase allosteric modulators of presenilin cleavage function (i.e., GSMs) offer an attractive therapeutic approach for AD. They represent a surgical strike on the presenilin-mediated production of longer, more-self-aggregating Aβ-peptides that ca
