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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

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 PS1 (P < 0.0001), PS2N141I (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV717I (one subject) mutations. Aβ ending at Aβ42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or P52 (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.

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Scheuner, D., Eckman, C., Jensen, M. et al. 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. Nat Med 2, 864–870 (1996). https://doi.org/10.1038/nm0896-864

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