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キーワード:
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要旨:
Proteolytic processing of the transmembrane domain of the amyloid precursor protein (APP) is a key component of Alzheimer's disease pathogenesis. Using C-terminally tagged APP derivatives, we have identified by amino-terminal sequencing a novel cleavage site of APP, at Leu-49, distal to the γ-secretase site. This was termed ε-cleavage. Brefeldin A treatment and pulse−chase experiments indicate that this cleavage occurs late in the secretory pathway. The level of ε-cleavage is decreased by expression of presenilin-1 mutants known to impair Aβ formation, and it is sensitive to the γ-secretase inhibitors MDL28170 and L-685,458. Remarkably, it shares similarities with site 3 cleavage of Notch-1: membrane topology, cleavage before a valine, dependence on presenilins, and inhibition profile.
