The Swedish mutation causes early-onset Alzheimer's disease by β-secretase cleavage within the secretory pathway

Abstract

Several missense mutations causing early-onset Alzheimer's disease (AD) have been described in the gene coding for the β-amyloid precursor protein (βAPP). A double mutation found in a Swedish family is located before the amyloid β-peptide (Aβ) region of βAPP and results in the increased production and secretion of Aβ. Here we show that the increased production of Aβ results from a cellular mechanism, which differs substantially from that responsible for the production of Aβ from wild-type βAPP. in the latter case, Aβ generation requires reinternalization and recycling of βAPP. In the case of the Swedish mutation the N-terminal β-secretase cleavage of Aβ occurs in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurs in the same compartment as the α-secretase cleavage, which normally prevents Aβ production, explaining the increased Aβ generation by a competition between α and β-secretase.