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

Full 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 beta-amyloid protein (Abeta) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Abeta 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 Abeta peptides in the brain. Most importantly, valsartan administration also attenuated the development of Abeta-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 Abeta-related memory deficits in subjects with AD or in those at high risk of developing AD.

Author information

Author/s: Wang, Jun (J); Ho, Lap (L); Chen, Linghong (L); Zhao, Zhong (Z); Zhao, Wei (W); Qian, Xianjuan (X); Humala, Nelson (N); Seror, Ilana (I); Bartholomew, Sadie (S); Rosendorff, Clive (C); Pasinetti, Giulio Maria (GM);

Affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.

Grants: AG02219 (Agency:NIA NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The Journal of clinical investigation (J Clin Invest), published in United States. (Language: eng)

Reference: 2007-Nov; vol 117 (issue 11) : pp 3393-402

Dates: Created 2007/11/02; Completed 2008/04/02; Revised 2008/11/20;

PMID: 17965777, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Alzheimer Disease - drug therapy; pathology; physiopathology
Amyloid beta-Protein - chemistry; genetics; metabolism
Amyloid beta-Protein Precursor - metabolism
Animals
Antihypertensive Agents - pharmacology; therapeutic use
Behavior, Animal - drug effects; physiology
Brain - drug effects; pathology; physiology
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug

Female
Humans
Memory - drug effects; physiology
Mice
Mice, Transgenic
Protein Structure, Quaternary
Random Allocation
Space Perception - drug effects; physiology
Tetrazoles - pharmacology; therapeutic use
Valine - analogs & derivatives; pharmacology; therapeutic use

Associated Chemicals: Amyloid beta-Protein (0) ; Amyloid beta-Protein Precursor (0) ; Antihypertensive Agents (0) ; Tetrazoles (0) ; valsartan (137862-53-4) ; Valine (7004-03-7)

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