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Harald Steiner on Semagacestat, a Pseudo γ-Secretase Inhibitor?

COMMENT This is a very important paper, showing the unexpected result that semagacestat causes the accumulation of longer Aβ species and short peptide byproducts that are produced by the sequential carboxy-terminal trimming activity of γ-secretase. The paper ...

Igor Kurochkin on Semagacestat, a Pseudo γ-Secretase Inhibitor?

COMMENT This is a very interesting study lending additional support for the hypothesis that increased intracellular Aβ is a major culprit of neurodegeneration and cognitive decline, while extracellular pool of Aβ plays relatively minor role. One obvious ...

Lili Zhang on Semagacestat, a Pseudo γ-Secretase Inhibitor?

COMMENT Based on the observations that semagacestat inhibited only secreted Aβ but not intracellular or Aβ byproducts, Tagami, et al. suggested that semagacestat is only a “pseudo” γ-secretase inhibitor (GSI). However, an obvious alternative interpretation of ...

Erik Portelius on Semagacestat, a Pseudo γ-Secretase Inhibitor?

COMMENT This is a comprehensive study that further shows the complexity of the processing of APP and Aβ. The authors have used several different cell lines and a mouse model to show that the γ-secretase inhibitor (GSI) semagacestat may not act as previously ...

Bart De Strooper on Semagacestat, a Pseudo γ-Secretase Inhibitor?

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). ...

Christoph Laske on Subjective Memory Complaints Tied to Tau

COMMENT The paper by Buckley et al. shows that higher subjective cognitive decline (SCD) scores are associated with higher tau burden in the brain in clinically healthy older adults. However, this finding does not yet justify considering SCD as an indicator for ...

Harald Hampel on Subjective Memory Complaints Tied to Tau

COMMENT Due to inconsistent results, it is still under debate whether subjective cognitive decline (SCD) represents an early sign of Alzheimer’s disease. Previous evidence showed that SCD was associated with future objective cognitive decline and conversion from ...

Boon-Seng Wong on ApoE4 Traps Insulin Receptor Inside Neurons

COMMENT The paper by Zhao et al. and other earlier findings have shown that ApoE4 impairs neuronal insulin signaling. In the current paper, the authors showed both recombinant ApoE3 and ApoE4 can bind to the insulin receptor, with ApoE4 having higher affinity. ...

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