17 RESULTS
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COMMENT We read with great interest the report by Xuefei Guo et al. We just published structures of γ-secretase in an apo state as well as in complex with the intermediate Aβ46 substrate. Comparing these two independent studies has been particularly exciting. The
COMMENT resolving the debate regarding FAD pathogenesis in this comment (Wolfe, 2015). The (FAD-linked)
COMMENT This study follows up on the intriguing observation that neuronal ApoE modulates Aβ production, originally reported by Wang et al., 2018. Here, Xianglong Hou et al. show that neuronally expressed ApoE-ε2 and ε3—but not ε4—lead to the intracellular accumul
COMMENT I read this extensive and comprehensive report by Lei Liu et al. with great interest. Indeed, this and our study present complementary data and insights, as well as tools for the quantitative assessment of familial and sporadic AD. In the context of famil
COMMENT I am saddened to hear that Dr. Steve Wagner passed away. I never had the pleasure of meeting him in person, but I find his work on γ-secretase modulators inspiring. My deepest condolences to his family. Lucia.ChavezGutierrez 0
COMMENT This sound study investigated the clinical association between shorter amyloid-β peptides (Aβ38 and Aβ40) and Alzheimer’s disease-related changes in two large, independent cohorts of biomarker-positive individuals who are spread across the AD spectrum. Th
COMMENT I have read this paper with great interest. The molecular (type of Aβ peptides), spatial, and temporal resolution data, as well as the longitudinal information provided by the study, are quite unique. The study confirms previous observations, such as the
COMMENT This paper presents SERP1 as a direct modulator of γ-secretase activity under ER stress, and highlights a potential pathogenic role for the SERP1-mediated upregulation of Aβ production in diabetes and in Alzheimer’s disease (AD). The authors convincingly
COMMENT The data generated by Tomita’s group supports the emerging view of a highly flexible and dynamic presenilin (PSEN) structure. Recent structural data has highlighted the conformational flexibility of the transmembrane domain (TMD) 2 of PSEN and uncovered c
COMMENT The co-localization of β-secretase, γ-secretase, and APP in ~5MDa high-molecular-weight complexes is clear and indeed raises the possibility of a coupled regulated intermembrane proteolysis (RIP) process. Interestingly, confocal microscopy (proximity liga
COMMENT I would like to start by congratulating Shi and colleagues for these recent achievements! These are exciting times for the γ-secretase field. The recent γ-secretase-substrate structures confirm what was anticipated by the previous co-structure of the γ-se
COMMENT High-resolution structures of γ-secretase have revealed the architecture of one of the most intriguing proteases. Moreover, co-structures with the allosteric inhibitor DAPT and a short co-purifying peptide uncovered the pocket and interaction mode for DAP
COMMENT Shi and colleagues delight us with the first atomic view of the γ-secretase complex! The atomic model shows many interesting features, but what I find most provocative and exciting is the plasticity/flexibility implied by this static view to make the stru
COMMENT I read with great interest this report from Yigong Shi's group. It reveals unexpected features of the γ-secretase structure and it raises many questions about the structure-function relationships in the protease complex, as many other excellent studi
COMMENT How mutations in PSEN1 cause AD is definitely an unresolved fundamental question in the AD field that Shen, Kelleher, and colleagues bring into discussion. The authors propose that pathogenic PSEN mutations cause AD via a loss of essential PSEN/γ-secretas
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