Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease
Jun Wang, … , Clive Rosendorff, Giulio Maria Pasinetti
Jun Wang, … , Clive Rosendorff, Giulio Maria Pasinetti
Published October 25, 2007
Citation Information: J Clin Invest. 2007;117(11):3393-3402. https://doi.org/10.1172/JCI31547.
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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 1

Valsartan prevents oligomerization of Aβ1–42 peptide into a HMW Aβ species in vitro.

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Valsartan prevents oligomerization of Aβ1–42 peptide into a HMW Aβ speci...
(A) Western blot analysis of Aβ1–42 oligomers in the presence of losartan, valsartan, carvedilol, hydralazine, propranolol, nicardipine, or amiloride. Bands at 3.5 kDa represent the monomeric Aβ form, whereas the smear between 55 and 130 kDa represents the oligomeric form of Aβ. (B) Valsartan decreases the accumulation of HMW Aβ1–42 species. Inset: Nonaggregated Aβ1–42 control (lane 1). Representative Western immunoblot of Aβ1–42 in the absence (lane 2) or presence of 10 μM valsartan (lane 3). (C) Quantitative dot blot analysis of valsartan inhibition of Aβ1–42 oligomerization. The same samples used in B were subjected to dot blot analysis using oligomer-specific antibody A11. Inset: Representative dot blot image. Results are expressed as percent of negative control (negative control presents nonaggregated Aβ), and values represent mean ± SEM. *P < 0.05.