Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease
Jun Wang, Lap Ho, Linghong Chen, Zhong Zhao, Wei Zhao, Xianjuan Qian, Nelson Humala, Ilana Seror, Sadie Bartholomew, Clive Rosendorff, Giulio Maria Pasinetti
Jun Wang, Lap Ho, Linghong Chen, Zhong Zhao, Wei Zhao, Xianjuan Qian, Nelson Humala, Ilana Seror, Sadie Bartholomew, Clive Rosendorff, Giulio Maria Pasinetti
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Research Article Neuroscience

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

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.

Authors

Jun Wang, Lap Ho, Linghong Chen, Zhong Zhao, Wei Zhao, Xianjuan Qian, Nelson Humala, Ilana Seror, Sadie Bartholomew, Clive Rosendorff, Giulio Maria Pasinetti

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Figure 2

Chronic valsartan treatment is highly tolerable in Tg2576 mice.

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Chronic valsartan treatment is highly tolerable in Tg2576 mice. Valsarta...
Valsartan was provided to female Tg2576 mice from 6 to 11.5 months of age at 10 mg/kg/d or 40 mg/kg/d. (A and B) Body weight and fluid consumption were monitored weekly. (C) Postprandial glucose tolerance response was examined after 5 months of valsartan treatment. (D) Tg2576 blood pressure measurements in response to approximately 5 months of valsartan treatments. (E) Baseline measurements of systolic and diastolic blood pressure and mean arterial blood pressure (MAP) in adult female Tg2576 mice and strain-, age-, sex-matched WT mice. The blood pressure determination for each animal was calculated as the mean of 10 individual measurements. Values represents group mean values ± SEM; n = 7–9 mice per group.