Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 (original) (raw)

• Letter
• Published: 24 October 1996
• Chris Eckman2,
• Cindy Zehr1,2,
• Xin Yu1,
• Cristian-Mihail Prada2,
• Jordi Perez-tur1,2,
• Mike Hutton1,2,
• Luc Buee3,
• Yasuo Harigaya2,
• Debra Yager2,
• David Morgan4,
• Marcia N. Gordon4,
• Leigh Holcomb4,
• Lawrence Refolo2,
• Brenda Zenk2,
• John Hardy1,2 &
• …
• Steven Younkin2

Nature volume 383, pages 710–713 (1996)Cite this article

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Abstract

MUTATIONS in the genes encoding amyloid-β precursor protein (APP)1 presenilin 1 (PS1)2 and presenilin 2 (PS2)3,4 are known to cause early-onset, autosomal dominant Alzheimer's disease. Studies of plasma and fibroblasts from subjects with these mutations have established that they all alter amyloid β-protein (βAPP) processing, which normally leads to the secretion of amyloid-β protein (relative molecular mass 4,000; _M_r 4K; ∼90% Aβ1–40, ∼10% Aβ1–42(43)), so that the extracellular concentration of Aβ42(43) is increased5. This increase in Aβ42(43) is believed to be the critical change that initiates Alzheimer's disease pathogenesis because Aβ42(43) is deposited early and selectively in the senile plaques that are observed in the brains of patients with all forms of the disease. To establish that the presenilin mutations increase the amount of Aβ42(43) in the brain and to test whether presenilin mutations act as true (gain of function) dominants, we have now constructed mice expressing wild-type and mutant presenilin genes. Analysis of these mice showed that overexpression of mutant, but not wild-type, PS1 selectively increases brain Aβ42(43). These results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of Aβ42(43) in the brain.

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Authors and Affiliations

1. Suncoast Alzheimer's Disease Laboratories, University of South Florida, Tampa, Florida, 33612, USA
   Karen Duff, Cindy Zehr, Xin Yu, Jordi Perez-tur, Mike Hutton & John Hardy
2. Birdsall Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224, USA
   Karen Duff, Chris Eckman, Cindy Zehr, Cristian-Mihail Prada, Jordi Perez-tur, Mike Hutton, Yasuo Harigaya, Debra Yager, Lawrence Refolo, Brenda Zenk, John Hardy & Steven Younkin
3. Unite 422 INSERM, Place de Verdun, 50945, Lille Cedex, France
   Luc Buee
4. Alzheimer's Research Laboratory, Department of Pharmacology, University of South Florida, Tampa, Florida, 33613, USA
   David Morgan, Marcia N. Gordon & Leigh Holcomb

Authors

1. Karen Duff
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2. Chris Eckman
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3. Cindy Zehr
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4. Xin Yu
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5. Cristian-Mihail Prada
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6. Jordi Perez-tur
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7. Mike Hutton
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8. Luc Buee
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9. Yasuo Harigaya
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10. Debra Yager
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11. David Morgan
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12. Marcia N. Gordon
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13. Leigh Holcomb
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14. Lawrence Refolo
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15. Brenda Zenk
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16. John Hardy
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17. Steven Younkin
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Duff, K., Eckman, C., Zehr, C. et al. Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1.Nature 383, 710–713 (1996). https://doi.org/10.1038/383710a0

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• Received: 27 August 1996
• Accepted: 25 September 1996
• Issue Date: 24 October 1996
• DOI: https://doi.org/10.1038/383710a0

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