This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 54/4/782    most recent HYPERTENSIONAHA.109.136879v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Tsukuda, K. Articles by Horiuchi, M. PubMed PubMed Citation Articles by Tsukuda, K. Articles by Horiuchi, M. Related Collections Animal models of human disease

(Hypertension. 2009;54:782.)
© 2009 American Heart Association, Inc.

Original Articles

Cognitive Deficit in Amyloid-β–Injected Mice Was Improved by Pretreatment With a Low Dose of Telmisartan Partly Because of Peroxisome Proliferator-Activated Receptor- Activation

Kana Tsukuda; Masaki Mogi; Jun Iwanami; Li-Juan Min; Akiko Sakata; Fei Jing; Masaru Iwai; Masatsugu Horiuchi

From the Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan.

Correspondence to Masatsugu Horiuchi, Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

The pathological hallmark of Alzheimer disease is deposition of amyloid-β protein (Aβ) in the brain. Telmisartan is a unique angiotensin II receptor blocker with peroxisome proliferator-activated receptor- (PPAR-)–stimulating activity. Activation of PPAR- is expected to prevent inflammation and Aβ accumulation in the brain. We investigated the possible preventive effect of telmisartan on cognitive decline in an Alzheimer disease mouse model via PPAR- activation. Here, male ddY mice underwent ICV injection of Aβ 1-40. Cognitive function was evaluated by the Morris water maze test. A low dose of telmisartan (0.35 mg/kg per day) was administered in drinking water with or without GW9662, a PPAR- antagonist. Cerebral blood flow was evaluated by laser speckle flowmetry. Inflammatory cytokine levels were measured by quantitative RT-PCR. Aβ 1-40 ICV injection significantly impaired cognitive function. Pretreatment with telmisartan improved this cognitive decline to a similar level to that in control mice. Cotreatment with GW9662, a PPAR- antagonist, attenuated this telmisartan-mediated improvement of cognition. Treatment with telmisartan enhanced cerebral blood flow and attenuated the Aβ-induced increase in expression of cytokines, such as tumor necrosis factor- and inducible NO synthase in the brain. Interestingly, coadministration of GW9662 cancelled these beneficial effects of telmisartan. Aβ 1-40 concentration in the brain was significantly decreased by treatment with telmisartan, whereas administration of GW9662 attenuated the decrease in telmisartan-mediated Aβ 1-40 concentration. Taken together, our findings suggest that even a low dose of telmisartan had a preventive effect on cognitive decline in an Alzheimer disease mouse model, partly because of PPAR- activation.

Key Words: Alzheimer disease • amyloid-β • cognitive impairment • PPAR • cerebral blood flow

This article has been cited by other articles:

				N.-C. Li, A. Lee, R. A Whitmer, M. Kivipelto, E. Lawler, L. E Kazis, and B. Wolozin Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis BMJ, January 12, 2010; 340(jan12_1): b5465 - b5465. [Abstract] [Full Text] [PDF]