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

• Published in: The Journal of clinical investigation Vol. 117; no. 11; pp. 3393 - 3402
• Main Authors: Wang, Jun, Ho, Lap, Chen, Linghong, Zhao, Zhong, Zhao, Wei, Qian, Xianjuan, Humala, Nelson, Seror, Ilana, Bartholomew, Sadie, Rosendorff, Clive, Pasinetti, Giulio Maria
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.11.2007
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Animals; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Behavior, Animal - drug effects; Behavior, Animal - physiology; Brain - drug effects; Brain - pathology; Brain - physiology; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Genetic aspects; Health aspects; Humans; Memory - drug effects; Memory - physiology; Mice; Mice, Transgenic; Protein Structure, Quaternary; Random Allocation; Space Perception - drug effects; Space Perception - physiology; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Valine - analogs & derivatives; Valine - pharmacology; Valine - therapeutic use; Valsartan; United States
• ISSN: 0021-9738
• DOI: 10.1172/JCI31547

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.