Beta-amyloid (Ab) deposition in the brain is the hallmark of Alzheimer's Disease (AD). To initiate Ab formation, b-secretase cleaves APP at the N-terminus of Ab to release APPsb (~100kD soluble NT-fragment), and C99, a 12-kD CT membrane fragment. Alternatively, a-secretase cleaves within the Ab to prevent the formation of Ab. Cleavage by a-secretase produces a soluble N-terminal fragment, APPsa, and a 10-kD membrane C-terminal fragment, C83. Both C99 and C83 can be further cleaved by g-secretase releasing Ab and a nonpathogenic p3 peptide, respectively. Both Presenilins and a newly discovered protein, Nicastrin are required for this activity. Nicastrin may act to position the APP stub correctly to allow presenilin to cut it at the right place; or it might regulate the activity of the g-secretase enzyme (possibly presenilin). Suppression of nicastrin expression in C. elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal fragment of b-APP, and alter the production of the amyloid b-peptide. Missense mutations in a conserved hydrophilic domain of nicastrin increase Ab42 and Ab40 peptide production, whereas deletions in this domain inhibit Ab production. It would thus appear that nicastrin and presenilins might be part of the multimeric protein complex "secretosme" necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and bAPP.

Human nicastrin gene (chromosome 1) encodes a transmembrane protein of 709 aa (mouse 708 aa). It has a putative signal peptide; a long N-terminal hydrophilic domain containing glycosylation, N-myristoylation and phosphorylation motifs; a 20-residue hydrophobic putative transmembrane domain; and a short hydrophilic carboxy terminus of 20 residues. Human nicastrin has 89% homology with the mouse and 30% with Drosophila's protein.

Human synthetic peptide

Highly purified

As reported

Supplied as a liquid in PBS, pH 7.2

95% conserved in mouse. No significantly sequence homology was detected with the C. elegans or drosophila protein

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