Protein Network of Nicastrin in Alzheimer's Disease

Gang Yu, PhD
University of Texas Southwestern (Dallas, TX)
Year Awarded:
Grant Duration:
April 1, 2003 to March 31, 2005
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Southern

Protein Network of Nicastrin in Alzheimer's Disease


A central event in the pathogenesis of Alzheimer's disease (AD) is the abnormal cleavage of the amyloid precursor protein, which gives rise to the amyloid beta peptides, the principle component of the amyloid plaques found in Alzheimer´s disease. The generation of amyloid beta peptides is dependent upon the behavior of presenilin-1 and presenilin-2 proteins, which can form partnerships with other proteins, one of which is nicastrin. The presenilin proteins and their partners, including nicastrin, work together to cut the amyloid precursor protein within a hydrophobic environment, with the subsequent release of amyloid beta peptides. If the action of presenilins and their partners are stopped, the neurotoxic amyloid beta peptides will not be released. Therefore, inhibiting the action of presenilins and their partners should result in stopping or at least slowing the progression of AD. The goals of Dr. Yu's study are to understand how nicastrin forms a partnership with presenilin and other molecules, and to use nicastrin as a bait to identify new proteins that may play important roles in amyloid beta peptide production. Understanding how presenilin interacts with its partners and uncovering novel nicastrin-binding mechanisms may help design better treatment strategies for Alzheimer´s disease and related disorders.


Shah, S., Lee, S.F., Tabucchi, K., Hao, Y.H., Yu, C., LaPlant, Q., Ball, H., Dann III, C.E., Sudhof, T., and Gang Yu, G. (2005) Nicastrin functions as a gamma-secretase-substrate receptor. Cell. 122(3):435-447. [Alzforum Recommended Paper]  

Lee, S.F., Shah, S., Yu, C., Wigley, W.C., Li, H., Lim, M., Pedersen, K., Han, W., Thomas, P., Lundkvist, J., Hao, Y.H., Yu, G. (2004) A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. J. Biol. Chem. 279(6):4144-52.  

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