Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease

D. Scheuner, C. Eckman, M. Jensen, X. Song, M. Citron, N. Suzuki, T. D. Bird, J. Hardy, M. Hutton, W. Kukull, E. Larson, E. Levy-Lahad, M. Viitanen, E. Peskind, P. Poorkaj, G. Schellenberg, R. Tanzi, W. Wasco, L. Lannfelt, D. SelkoeS. Younkin

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Abstract

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid [β-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid β-protein (Aβ) ending at Aβ42(43) in vivo, we performed a blinded comparison of plasma Aβ levels in carriers of these mutations and controls. Aβ1-42(43) was elevated in plasma from subjects with FAD-linked PSI (P < 0.0001), PS2(N1411) (P = 0.009), APP(K670N,M671L) (P < 0.0001), and APP(V7171) (one subject) mutations. Aβ ending at A1β42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzheimer's disease by increasing the extracellular concentration of Aβ42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

Original languageEnglish (US)
Pages (from-to)864-870
Number of pages7
JournalNature Medicine
Volume2
Issue number8
DOIs
StatePublished - Sep 18 1996

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., Larson, E., Levy-Lahad, E., Viitanen, M., Peskind, E., Poorkaj, P., Schellenberg, G., Tanzi, R., Wasco, W., Lannfelt, L., ... Younkin, S. (1996). Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Medicine, 2(8), 864-870. https://doi.org/10.1038/nm0896-864