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Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models.

Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W - J. Exp. Med. (2008)

Bottom Line: The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD.We found that VPA decreased Abeta production by inhibiting GSK-3beta-mediated gamma-secretase cleavage of APP both in vitro and in vivo.Our study suggests that VPA may be beneficial in the prevention and treatment of AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Townsend Family Laboratories, Brain Research Center, University of British Columbia, Vancouver, BC, Canada.

ABSTRACT
Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid beta-protein (Abeta), the central component of neuritic plaques, is derived from beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Abeta production by inhibiting GSK-3beta-mediated gamma-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.

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Related in: MedlinePlus

VPA improves memory deficits in AD transgenic mice. A Morris water maze test consists of 1 d of visible platform tests and 4 d of hidden platform tests, plus a probe trial 24 h after the last hidden platform test. Animal movement was tracked and recorded by HVS 2020 Plus image analyzer. The 7-mo APP23 age group mice were tested after 1 mo of daily VPA (n = 30 mice) or vehicle solution (n = 30 mice) injections. (A) During the first day of visible platform tests, the VPA-treated and control APP23 mice exhibited a similar latency to escape onto the visible platform. P > 0.05 by Student's t test. (B) The VPA-treated and control APP23 mice had similar swimming distances before escaping onto the visible platform in the visible platform test. P > 0.05 by Student's t test. (C) In hidden platform tests, mice were trained with 6 trials per day for 4 d. VPA-treated APP23 mice showed a shorter latency to escape onto the hidden platform on the third and fourth day. P < 0.001 by ANOVA. (D) The VPA-treated APP23 mice had a shorter swimming length before escaping onto the hidden platform on the third and fourth day. P < 0.01 by ANOVA. (E) In the probe trial on the sixth day, the VPA-treated APP23 mice traveled into the third quadrant, where the hidden platform was previously placed, significantly more times than controls. *, P < 0.005 by Student's t test.
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fig2: VPA improves memory deficits in AD transgenic mice. A Morris water maze test consists of 1 d of visible platform tests and 4 d of hidden platform tests, plus a probe trial 24 h after the last hidden platform test. Animal movement was tracked and recorded by HVS 2020 Plus image analyzer. The 7-mo APP23 age group mice were tested after 1 mo of daily VPA (n = 30 mice) or vehicle solution (n = 30 mice) injections. (A) During the first day of visible platform tests, the VPA-treated and control APP23 mice exhibited a similar latency to escape onto the visible platform. P > 0.05 by Student's t test. (B) The VPA-treated and control APP23 mice had similar swimming distances before escaping onto the visible platform in the visible platform test. P > 0.05 by Student's t test. (C) In hidden platform tests, mice were trained with 6 trials per day for 4 d. VPA-treated APP23 mice showed a shorter latency to escape onto the hidden platform on the third and fourth day. P < 0.001 by ANOVA. (D) The VPA-treated APP23 mice had a shorter swimming length before escaping onto the hidden platform on the third and fourth day. P < 0.01 by ANOVA. (E) In the probe trial on the sixth day, the VPA-treated APP23 mice traveled into the third quadrant, where the hidden platform was previously placed, significantly more times than controls. *, P < 0.005 by Student's t test.

Mentions: To investigate whether VPA treatment affects learning and memory in AD pathogenesis, behavioral tests were performed after APP23 mice received 1 mo of VPA treatment starting at the age of 7 mo. The Morris water maze was used to determine the effect of VPA on spatial memory. In the visible platform tests, VPA-treated and control APP23 mice had similar escape latency (53.190 ± 1.56 and 49.75 ± 2.47 s; P > 0.05; Fig. 2 A) and path length (7.03 ± 1.33 and 6.78 ± 1.60 s; P > 0.05; Fig. 2 B), which indicated that VPA treatment did not affect mouse motility or vision. In the hidden platform-swimming test, APP23 mice treated with VPA showed significant improvements compared with the vehicle-treated controls. The escape latency on the third and fourth day of the hidden platform test was shorter (15.95 ± 1.61 and 12.80 ± 1.83 s) than nontreated APP23 mice (29.04 ± 2.99 and 24.89 ± 3.33 s; P < 0.001; Fig. 3 C). The VPA-treated mice were able to swim significantly shorter distances to reach the platform (3.88 ± 0.91 and 2.68 ± 1.02 m) compared with control mice (6.03 ± 0.94 and 5.37 ± 1.38 m) on the third and fourth day (P < 0.01; Fig. 2 D). In the probe trial on the last day of testing, the platform was removed. VPA treatment significantly improved the AD mouse's spatial memory. The number of times the mice traveled into the third quadrant, where the hidden platform was previously placed, was significantly greater with VPA treatment compared with control (9.56 ± 2.62 and 4.18 ± 1.06; P < 0.005; Fig. 2 E). These data indicate that VPA treatment significantly improves the memory deficits seen in APP23 mice. Because VPA treatment stopped a day before and there was no treatment during the behavioral testing, the effect of VPA on the behavioral performance in the mice was not just acute, but also long lasting.


Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models.

Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W - J. Exp. Med. (2008)

VPA improves memory deficits in AD transgenic mice. A Morris water maze test consists of 1 d of visible platform tests and 4 d of hidden platform tests, plus a probe trial 24 h after the last hidden platform test. Animal movement was tracked and recorded by HVS 2020 Plus image analyzer. The 7-mo APP23 age group mice were tested after 1 mo of daily VPA (n = 30 mice) or vehicle solution (n = 30 mice) injections. (A) During the first day of visible platform tests, the VPA-treated and control APP23 mice exhibited a similar latency to escape onto the visible platform. P > 0.05 by Student's t test. (B) The VPA-treated and control APP23 mice had similar swimming distances before escaping onto the visible platform in the visible platform test. P > 0.05 by Student's t test. (C) In hidden platform tests, mice were trained with 6 trials per day for 4 d. VPA-treated APP23 mice showed a shorter latency to escape onto the hidden platform on the third and fourth day. P < 0.001 by ANOVA. (D) The VPA-treated APP23 mice had a shorter swimming length before escaping onto the hidden platform on the third and fourth day. P < 0.01 by ANOVA. (E) In the probe trial on the sixth day, the VPA-treated APP23 mice traveled into the third quadrant, where the hidden platform was previously placed, significantly more times than controls. *, P < 0.005 by Student's t test.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2585842&req=5

fig2: VPA improves memory deficits in AD transgenic mice. A Morris water maze test consists of 1 d of visible platform tests and 4 d of hidden platform tests, plus a probe trial 24 h after the last hidden platform test. Animal movement was tracked and recorded by HVS 2020 Plus image analyzer. The 7-mo APP23 age group mice were tested after 1 mo of daily VPA (n = 30 mice) or vehicle solution (n = 30 mice) injections. (A) During the first day of visible platform tests, the VPA-treated and control APP23 mice exhibited a similar latency to escape onto the visible platform. P > 0.05 by Student's t test. (B) The VPA-treated and control APP23 mice had similar swimming distances before escaping onto the visible platform in the visible platform test. P > 0.05 by Student's t test. (C) In hidden platform tests, mice were trained with 6 trials per day for 4 d. VPA-treated APP23 mice showed a shorter latency to escape onto the hidden platform on the third and fourth day. P < 0.001 by ANOVA. (D) The VPA-treated APP23 mice had a shorter swimming length before escaping onto the hidden platform on the third and fourth day. P < 0.01 by ANOVA. (E) In the probe trial on the sixth day, the VPA-treated APP23 mice traveled into the third quadrant, where the hidden platform was previously placed, significantly more times than controls. *, P < 0.005 by Student's t test.
Mentions: To investigate whether VPA treatment affects learning and memory in AD pathogenesis, behavioral tests were performed after APP23 mice received 1 mo of VPA treatment starting at the age of 7 mo. The Morris water maze was used to determine the effect of VPA on spatial memory. In the visible platform tests, VPA-treated and control APP23 mice had similar escape latency (53.190 ± 1.56 and 49.75 ± 2.47 s; P > 0.05; Fig. 2 A) and path length (7.03 ± 1.33 and 6.78 ± 1.60 s; P > 0.05; Fig. 2 B), which indicated that VPA treatment did not affect mouse motility or vision. In the hidden platform-swimming test, APP23 mice treated with VPA showed significant improvements compared with the vehicle-treated controls. The escape latency on the third and fourth day of the hidden platform test was shorter (15.95 ± 1.61 and 12.80 ± 1.83 s) than nontreated APP23 mice (29.04 ± 2.99 and 24.89 ± 3.33 s; P < 0.001; Fig. 3 C). The VPA-treated mice were able to swim significantly shorter distances to reach the platform (3.88 ± 0.91 and 2.68 ± 1.02 m) compared with control mice (6.03 ± 0.94 and 5.37 ± 1.38 m) on the third and fourth day (P < 0.01; Fig. 2 D). In the probe trial on the last day of testing, the platform was removed. VPA treatment significantly improved the AD mouse's spatial memory. The number of times the mice traveled into the third quadrant, where the hidden platform was previously placed, was significantly greater with VPA treatment compared with control (9.56 ± 2.62 and 4.18 ± 1.06; P < 0.005; Fig. 2 E). These data indicate that VPA treatment significantly improves the memory deficits seen in APP23 mice. Because VPA treatment stopped a day before and there was no treatment during the behavioral testing, the effect of VPA on the behavioral performance in the mice was not just acute, but also long lasting.

Bottom Line: The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD.We found that VPA decreased Abeta production by inhibiting GSK-3beta-mediated gamma-secretase cleavage of APP both in vitro and in vivo.Our study suggests that VPA may be beneficial in the prevention and treatment of AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Townsend Family Laboratories, Brain Research Center, University of British Columbia, Vancouver, BC, Canada.

ABSTRACT
Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid beta-protein (Abeta), the central component of neuritic plaques, is derived from beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Abeta production by inhibiting GSK-3beta-mediated gamma-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.

Show MeSH
Related in: MedlinePlus