Nature Medicine


	article

August 1996
Table of
Contents

August 1996 Volume 2 Number 8 p864

Secreted amyloid beta-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. Scheuner¹, C. Eckman^1,2, M. Jensen³, X. Song⁴, M. Citron⁵, N. Suzuki⁶, T.D. Bird^7,12, J. Hardy¹⁴, M. Hutton¹⁴, W. Kukull⁸, E. Larson⁹, E. Levy-Lahad^9,13, M. Viitanen³, E. Peskind^10,13, P. Poorkaj^7,13, G. Schellenberg^7,9,11,13, R. Tanzi¹⁵, W. Wasco¹⁵, L. Lannfelt³, D. Selkoe⁵ & S. Younkin²

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A-beta) ending at A-beta42(43) in vivo, we performed a blinded comparison of plasma A-beta levels in carriers of these mutations and controls. A-beta1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P<0.0001), PS2_N141I (P=0.009), APP_K670N,M671L (P<0.0001), and APP_V717I (one subject) mutations. A-beta ending at A-beta42(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 A-beta42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

¹1Department of Neuroscience, Case Western Reserve University, Cleveland, Ohio 44106, USA
²Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
³Karolinska Institute, Department of Clinical Neuroscience and Family Medicine, Huddinge University Hospital, Novum KFC, S-141 86 Huddinge, Sweden
⁴Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
⁵Center for Neurologic Diseases, Harvard Medical School and Brigham and Women�s Hospital, Boston, Massachusetts 02115, USA
⁶Discovery Research Division, Takeda Chemical Industries, Ltd., Wadai 10, 300-42 Tsukuba, Ibaraki, Japan
⁷Department of Neurology, ⁸Department of Epidemiology, ⁹Department of Medicine, ¹⁰Department of Psychiatry and Behavioral Sciences & ¹¹Department of Pharmacology, University of Washington, Seattle, Washington 98185, USA
¹²Neurology Service and ¹³Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound ¹⁴Health Care System, Seattle, Washington 98108, USA
Suncoast Alzheimer�s Disease Laboratories, Department of Psychiatry, University of South Florida, Tampa, Florida 33613, USA
¹⁵Genetics and Aging Unit, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Charlestown, Massachusetts 02129, USA
D. Scheuner present address: Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, USA
D. Scheuner, C.E., M.J. and X.S. contributed equally to this study.
Correspondence should be addressed to S.Y.