THE SWEDISH MUTATION CAUSES EARLY-ONSET ALZHEIMERS-DISEASE BY BETA-SECRETASE CLEAVAGE WITHIN THE SECRETORY PATHWAY

Several missense mutations causing early-onset Alzheimer's disease (AD ) have been described in the gene coding for the beta-amyloid precurso r protein (beta APP). A double mutation found in a Swedish family is l ocated 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 m echanism, which differs substantially from that responsible for the pr oduction of A beta from wild-type beta APP. In the latter case, A beta generation requires reinternalization and recycling of beta APP. In t he case of the Swedish mutation the N-terminal beta-secretase cleavage of A beta occurs in Golgi-derived vesicles, most likely within secret ory vesicles. Therefore, this cleavage occurs in the same compartment as the alpha-secretase cleavage, which normally prevents A beta produc tion,explaining the increased A beta generation by a competition betwe en alpha- and beta-secretase.