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  • Title: Intracellular domain generation of amyloid precursor protein by epsilon-cleavage depends on C-terminal fragment by alpha-secretase cleavage.
    Author: Kume H, Maruyama K, Kametani F.
    Journal: Int J Mol Med; 2004 Jan; 13(1):121-5. PubMed ID: 14654982.
    Abstract:
    A significant accumulation of Abeta is major pathological feature in the brain in patients with Alzheimer's disease (AD). Amyloid precursor protein (APP) is cleaved by alpha- and beta-secretase, resulting in secretion of extracellular domain. Then the remaining membrane-anchored C-terminal fragments (CTFalpha or CTFbeta) are cleaved by gamma-secretase. Therefore, Abeta is derived from APP by sequential proteolytic processing involving 2 proteases, called beta- and gamma-secretase. Gamma-secretase cleavage results in the generation of the APP intracellular domain (AICD), as well as Abeta. Recently, AICD is generated by epsilon-cleavage site near the cytoplasmic membrane boundary of APP, not by gamma-cleavage site in the middle of transmembrane domain. We show that elevated beta-secretase levels induced the increase in CTFbeta and Abeta generation and reduction of CTFalpha and AICD generation in vitro. Furthermore, elevated alpha-secretase levels induced an increase of AICD. The results suggest that generation of AICD by epsilon-cleavage depends on CTFalpha and that gamma- and epsilon-cleavage are differentially regulated.
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