Valsartan lowers brain ß-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease
Jun Wang1, Lap Ho1,2, Linghong Chen1, Zhong Zhao1, Wei Zhao1, Xianjuan Qian1, Nelson Humala1, Ilana Seror1, Sadie Bartholomew1, Clive Rosendorff3 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.
Received for publication January 18, 2007, and accepted in revised form August 28, 2007.
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The abstract and discussion sections of the article are below. Jason
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 ß-amyloid protein (Aß) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Aß 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 Aß peptides in the brain. Most importantly, valsartan administration also attenuated the development of Aß-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 Aß-related memory deficits in subjects with AD or in those at high risk of developing AD.
Discussion
This study was designed primarily in response to a series of epidemiological and clinical studies reporting mixed results on the association of the use of antihypertensive drugs and AD incidence (1–5). To clarify whether any of the currently available antihypertensive medications could provide beneficial AD-modifying activity, we surveyed 55 antihypertensive drugs for their potential beneficial role in AD-type amyloid neuropathology. Seven of these were identified to significantly reduce Aß accumulation in vitro. Among these 7 drugs tested for antioligomerization activity, we found valsartan, and to a lesser extent losartan, to be the only drugs capable of attenuating oligomerization of Aß peptides into soluble HMW oligomeric Aß species in vitro.
Valsartan treatment prevents Aß-related spatial memory reference deficits and AD-type neuropathology in vivo at doses equivalent to or lower than the recommended dose for humans. In our study we found that treatment of Tg2576 mice with valsartan at a concentration as low as 10 mg/kg/d attenuated spatial reference memory deterioration that coincided with an approximately 3-fold reduction in HMW Aß peptide content in the brain, while IDE activity and the content of total Aß1–42 (but not total Aß1–40) were unaffected. We hypothesize that treatment with the low valsartan dose most likely beneficially influences AD-type spatial memory deterioration through direct interaction of valsartan with Aß peptides in the brain (as we found in vitro) and prevents the generation of soluble, extracellular HMW Aß species. This activity is independent of IDE promotion. This scenario is consistent with the recent study showing that extracellular, soluble HMW oligomeric Aß peptides purified from the brain of middle-aged, impaired Tg2576 mice could disrupt memory functions, even episodically, when administered to normal rats (18). In addition to preventing Aß oligomerization, we found that the higher dose of valsartan (40 mg/kg/d) also significantly promoted CM-IDE activity in the cerebral cortex of Tg2576 mice. This increase in CM-IDE activity was highly selective, as there was no detectable change in other proteases involved in the clearance of Aß (e.g., neprilysin and ECE). Thus at the higher dose, valsartan most likely benefited spatial memory functions in Tg2576 mice by simultaneously increasing Aß degradation by IDE and reducing Aß aggregation into soluble, extracellular HMW Aß species.
Finally, an additional mechanism through which valsartan prevents Aß-related spatial memory impairment and AD-type neuropathology may be through the promotion of Aß “sinking” from the brain to the periphery, as suggested by the decreased level of serum Aß in valsartan-treated Tg2576 mice. However, our results did not reach statistical significance. Additional studies will clarify whether valsartan treatment may also reduce Aß neuropathology by promoting Aß sinking from the brain to the periphery.
Collectively, our evidence suggests that valsartan treatment might prevent Aß-related spatial memory reference deficits in the Tg2576 AD mouse model through a combination of multiple mechanisms: (a) reducing Aß aggregation into HMW Aß species; (b) increasing Aß degradation by IDE; and possibly (c) promoting sinking of Aß peptides from the brain to the periphery.
Valsartan beneficially prevented Aß-related spatial memory reference deficit in Tg2576 mice at a dose less than the equivalent recommended clinical dose for hypertensive treatment. While there are as yet no data in humans to support the idea that angiotensin receptor–blocking drug valsartan has any impact on the incidence or progression of cognitive impairment, this study may provide the appropriate impetus for clinical trials in vulnerable human subjects, such as patients with mild cognitive impairment, at subclinical doses.
Aside from valsartan, we identified 6 antihypertensive drugs that significantly reduced accumulations of Aß peptides in vitro in primary Tg2576 cortico-hippocampal neuron cultures. While our evidence supports the in vivo efficacy of valsartan to attenuate AD-type phenotypes in Tg2576 AD mouse model, we have not yet determined the in vivo efficacy of the other 6 Aß-lowering antihypertensive drugs. Many factors, including biological availability and drug metabolism, may influence Aß-lowering activity of a drug in vivo. It would not be surprising if some drugs that are biologically active in vitro were not effective in vivo. Thus, individual drugs must be investigated on a case-by-case basis. Ongoing studies in our laboratory are evaluating the remaining 6 antihypertensives individually for their in vivo efficacy to protect against progressive Aß neuropathology and Aß-related memory deficits in AD. |
