Study of generation of Alzheimer's amyloid β peptide

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Processing of the amyloid precursor protein (APP) includes αand βcleavage pathways. The proteolytic product of the APP, Aβ is generated through initial β cleavage and subsequent γ cleavage pathway. Aβ is considered central in the pathogenesis of Alzheimer's disease, and therefore clarification of the APP processing is an important issue. In our previous study performed in 2001, we demonstrated that the possibility is quite low that APP undergoes processing consisting of γ cleavage prior to α/β cleavage. Namely APP is subject uniquely to the processing consisting of initial α/β cleavage and subsequent γ cleavage pathway. Based on these results, we studied the eubcellular compartments for α and β cleavages. First APP molecule was modified by addition of the Retargeting motif, which restricts the molecule to be expressed in ER without sorting to afterward compartments. This mutant APP was found to give α and β cleavages. Second APP processing in ER was reconstructed using brefeldin A, an agent that destructs Golgi apparatus and thereby inhibits sorting out from ER of expressed proteins. Under this condition APP was found to show α but not β cleavage. Thus APP expressed restrictedly in ER shows a cleavage. The cell surface has been identified as the subcellular site for α cleavage to occur. Here ER was identified another subcellular site for α cleavage.