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The Journal of Neuroscience, April 15, 2003, 23(8):3272

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

Tong Li¹, Guojun Ma^{1, 2}, Huaibin Cai¹, Donald L. Price^{1, 2, 3}, and Philip C. Wong^{1, 2}

Departments of ¹ Pathology, ² Neuroscience, and ³ Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Recent studies indicate that nicastrin (NCT) and presenilins form functional components of a multimeric -secretase complex required for the regulated intramembraneous proteolysis of Notch and -amyloid (A) 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/-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 A peptides is abolished in NCT^/ fibroblasts, whereas it is reduced by ~50% in NCT^+/ cells; the failure to generate A peptides in NCT^/ cells is accompanied by destabilization of the presenilin/-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 -secretase complex in mammals required for both -secretase activity and APP trafficking and suggest that nicastrin may be a valuable therapeutic target for Alzheimer's disease.

Key words: nicastrin knock-out mice; nicastrin-deficient fibroblasts; presenilin/-secretase complex; Notch signaling; APP processing and trafficking; Alzheimer's disease

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2383272-06$05.00/0

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