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Home/Research/Paper Chase/The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway.
The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway.
Nat. Med..12 1, 1995;1(12):1291-6.
Haass C, Lemere CA, Capell A, Citron M, Seubert P, Schenk D, Lannfelt L, Selkoe DJ.
Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital Boston, Massachusetts 02115, USA.
Several missense mutations causing early-onset Alzheimer's disease (AD) have been described in the gene coding for the beta-amyloid precursor protein (beta APP). A double mutation found in a Swedish family is located before the amyloid beta-peptide (A beta) region of beta APP and results in the increased production and secretion of A beta. Here we show that the increased production of A beta results from a cellular mechanism, which differs substantially from that responsible for the production of A beta from wild-type beta APP. In the latter case, A beta generation requires reinternalization and recycling of beta APP. In the case of the Swedish mutation the N-terminal beta-secretase cleavage of A beta occurs in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurs in the same compartment as the alpha-secretase cleavage, which normally prevents A beta production, explaining the increased A beta generation by a competition between alpha- and beta-secretase.