English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Recent studies indicate that nicastrin (NCT) and presenilins form functional components of a multimeric γ-secretase complex required for the regulated intramembraneous proteolysis of Notch and β-amyloid (Aβ) precursor protein (APP). To determine whether nicastrin is required for proteolytic processing of Notch and APP in mammals and the role of nicastrin in presenilin/γ-secretase complex assembly, we generated nicastrin-deficient (NCT−/−) mice and derived fibroblasts from NCT−/− embryos. Nicastrin-null embryos died by embryonic day 10.5 and exhibited several patterning defects, including abnormal somite segmentation, phenotypes that are reminiscent of embryos lacking Notch1 or both presenilins. Importantly, secretion of Aβ peptides is abolished inNCT−/− fibroblasts, whereas it is reduced by ∼50% in NCT+/− cells; the failure to generate Aβ peptides inNCT−/− cells is accompanied by destabilization of the presenilin/γ-secretase complex and accumulation of APP–C-terminal fragments. Moreover, APP trafficking analysis in NCT−/−fibroblasts revealed a significant delay in the rate of APP reinternalization compared with that of control cells. Together, these results establish that nicastrin is an essential component of the multimeric γ-secretase complex in mammals required for both γ-secretase activity and APP trafficking and suggest that nicastrin may be a valuable therapeutic target for Alzheimer's disease.

the journal of neuroscience/the journal of neuroscience

Nicastrin Is Required for Assembly of Presenilin/γ-Secretase Complexes to Mediate Notch Signaling and for Processing and Trafficking of β-Amyloid Precursor Protein in Mammals