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Research ArticleNeuroscience Free access | 10.1172/JCI31547

Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease

Jun Wang,1 Lap Ho,1,2 Linghong Chen,1 Zhong Zhao,1 Wei Zhao,1 Xianjuan Qian,1 Nelson Humala,1 Ilana Seror,1 Sadie Bartholomew,1 Clive Rosendorff,3 and Giulio Maria Pasinetti1,2,4

1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

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1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

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1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

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1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

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1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

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1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

Find articles by Qian, X. in: PubMed | Google Scholar

1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

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1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

Find articles by Seror, I. in: PubMed | Google Scholar

1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

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1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

Find articles by Rosendorff, C. in: PubMed | Google Scholar

1Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. 2Geriatric Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 3Department of Medicine, Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center, New York, New York, USA. 4Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

Address correspondence to: Giulio Maria Pasinetti, Icahn Research Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1230, New York, New York 10029, USA. Phone: (212) 659-8716 or (212) 659-8740; Fax: (212) 876-9042; E-mail: giulio.pasinetti@mssm.edu.

Find articles by Pasinetti, G. in: PubMed | Google Scholar

Published October 25, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI31547.
© 2007 The American Society for Clinical Investigation
Published October 25, 2007 - Version history
Received: January 18, 2007; Accepted: August 28, 2007
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Abstract

Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type β-amyloid protein (Aβ) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Aβ peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric Aβ peptides in the brain. Most importantly, valsartan administration also attenuated the development of Aβ-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive Aβ-related memory deficits in subjects with AD or in those at high risk of developing AD.

Version history
  • Version 1 (October 25, 2007): No description
  • Version 2 (November 1, 2007): No description
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