A significant accumulation of Aβ is major pathological feature in the brain in patients with Alzheimer's disease (AD). Amyloid precursor protein (APP) is cleaved by α- and β-secretase, resulting in secretion of extracellular domain. Then the remaining membrane-anchored C-terminal fragments (CTFα or CTFβ) are cleaved by γ-secretase. Therefore, Aβ is derived from APP by sequential proteolytic processing involving 2 proteases, called β- and γ-secretase. γ-Secretase cleavage results in the generation of the APP intracellular domain (AICD), as well as Aβ. Recently, AICD is generated by ε-cleavage site near the cytoplasmic membrane boundary of APP, not by γ-cleavage site in the middle of transmembrane domain. We show that elevated β-secretase levels induced the increase in CTFβ and Aβ generation and reduction of CTFα and AICD generation in vitro. Furthermore, elevated α-secretase levels induced an increase of AICD. The results suggest that generation of AICD by ε-cleavage depends on CTFα and that γ- and ε-cleavage are differentially regulated.

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