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A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice.

Niikura T, Sidahmed E, Hirata-Fukae C, Aisen PS, Matsuoka Y - PLoS ONE (2011)

Bottom Line: We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains.NEP activity was also elevated by S14G-HN treatment in vitro.Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. tniikura@sfu.ca

ABSTRACT
Humanin (HN), a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD)-related cytotoxicities, including exposure to amyloid beta (Abeta), in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APP(swe), tau(P310L), and PS-1(M146V) that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G-HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD.

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The effect of S14G-HN on spatial memory in 3xTg-AD mice.Male and female 3xTg-AD mice were subjected to Morris Water Maze after 3 months of intranasal administration with S14G-HN or vehicle. A. Training sessions. Training trials (120 sec each) were performed twice a day for 5 days. Time spent to find platform in first trial in each day is shown as mean±SEM. B–D. Probe test. Time spent in each quadrant is shown as mean±SEM (B). Mice which did not find the visual platform were considered abnormal mice and data of these mice was excluded from analysis (vehicle male = 3, female = 2, S14G-HN male = 1, female = 2). P values of non-parametric ANOVA test (Kruskal-Wallis test) are shown. Time spent within 60 cm from the platform region during first 60 seconds of probe test is shown as mean±SEM (C). Time spent within platform area during first 30 seconds of probe test is shown as mean±SEM (D). In C and D, p =  indicates p values of Mann-Whitney U test.
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pone-0016259-g003: The effect of S14G-HN on spatial memory in 3xTg-AD mice.Male and female 3xTg-AD mice were subjected to Morris Water Maze after 3 months of intranasal administration with S14G-HN or vehicle. A. Training sessions. Training trials (120 sec each) were performed twice a day for 5 days. Time spent to find platform in first trial in each day is shown as mean±SEM. B–D. Probe test. Time spent in each quadrant is shown as mean±SEM (B). Mice which did not find the visual platform were considered abnormal mice and data of these mice was excluded from analysis (vehicle male = 3, female = 2, S14G-HN male = 1, female = 2). P values of non-parametric ANOVA test (Kruskal-Wallis test) are shown. Time spent within 60 cm from the platform region during first 60 seconds of probe test is shown as mean±SEM (C). Time spent within platform area during first 30 seconds of probe test is shown as mean±SEM (D). In C and D, p =  indicates p values of Mann-Whitney U test.

Mentions: In the Morris water maze test, training trials (2 min each) were performed twice a day for 5 days. To assess flexible learning ability, the position of the platform was rotated everyday. The parameter of learning flexibility was analyzed by looking at the block of first trials performed each day (Fig. 3A). S14G-HN treated male mice showed a trend of shorter latency than control on the second day. In female mice, no significant difference was observed between S14G-HN-treated and control mice. On the fifth day, the probe test was performed after the second daily trial. Time spent in each quadrant of pool was significantly different in S14G-HN treated male mice but not in vehicle control male mice by non-parametric ANOVA (Fig. 3B). Post-hoc test on values of S14G-HN-treated male mice detected a significant difference between platform quadrant and opposite quadrant (p<0.05). Consistently, time spent in the area within 60 cm from the platform location was significantly longer for S14G-HN treated male mice than for vehicle control mice (Fig. 3C). These results show that S14G-HN-treated male mice stayed close to the platform location longer than vehicle control mice, suggesting better cognitive and memory function of S14G-HN-treated mice than control. We also measured the duration that mice spent in the platform location (Fig. 3D). In the first 30 sec of probe test, S14G-HN-treated male mice stayed in the platform area significantly longer than control male mice. S14G-HN treated female mice showed a trend similar to the male mice, though the difference was not significant (Fig. 3B–D). Swimming speeds of S14G-HN treated and control mice were virtually the same in probe test (data not shown), indicating that locomotion activity was not affected by S14G-HN.


A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice.

Niikura T, Sidahmed E, Hirata-Fukae C, Aisen PS, Matsuoka Y - PLoS ONE (2011)

The effect of S14G-HN on spatial memory in 3xTg-AD mice.Male and female 3xTg-AD mice were subjected to Morris Water Maze after 3 months of intranasal administration with S14G-HN or vehicle. A. Training sessions. Training trials (120 sec each) were performed twice a day for 5 days. Time spent to find platform in first trial in each day is shown as mean±SEM. B–D. Probe test. Time spent in each quadrant is shown as mean±SEM (B). Mice which did not find the visual platform were considered abnormal mice and data of these mice was excluded from analysis (vehicle male = 3, female = 2, S14G-HN male = 1, female = 2). P values of non-parametric ANOVA test (Kruskal-Wallis test) are shown. Time spent within 60 cm from the platform region during first 60 seconds of probe test is shown as mean±SEM (C). Time spent within platform area during first 30 seconds of probe test is shown as mean±SEM (D). In C and D, p =  indicates p values of Mann-Whitney U test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3022031&req=5

pone-0016259-g003: The effect of S14G-HN on spatial memory in 3xTg-AD mice.Male and female 3xTg-AD mice were subjected to Morris Water Maze after 3 months of intranasal administration with S14G-HN or vehicle. A. Training sessions. Training trials (120 sec each) were performed twice a day for 5 days. Time spent to find platform in first trial in each day is shown as mean±SEM. B–D. Probe test. Time spent in each quadrant is shown as mean±SEM (B). Mice which did not find the visual platform were considered abnormal mice and data of these mice was excluded from analysis (vehicle male = 3, female = 2, S14G-HN male = 1, female = 2). P values of non-parametric ANOVA test (Kruskal-Wallis test) are shown. Time spent within 60 cm from the platform region during first 60 seconds of probe test is shown as mean±SEM (C). Time spent within platform area during first 30 seconds of probe test is shown as mean±SEM (D). In C and D, p =  indicates p values of Mann-Whitney U test.
Mentions: In the Morris water maze test, training trials (2 min each) were performed twice a day for 5 days. To assess flexible learning ability, the position of the platform was rotated everyday. The parameter of learning flexibility was analyzed by looking at the block of first trials performed each day (Fig. 3A). S14G-HN treated male mice showed a trend of shorter latency than control on the second day. In female mice, no significant difference was observed between S14G-HN-treated and control mice. On the fifth day, the probe test was performed after the second daily trial. Time spent in each quadrant of pool was significantly different in S14G-HN treated male mice but not in vehicle control male mice by non-parametric ANOVA (Fig. 3B). Post-hoc test on values of S14G-HN-treated male mice detected a significant difference between platform quadrant and opposite quadrant (p<0.05). Consistently, time spent in the area within 60 cm from the platform location was significantly longer for S14G-HN treated male mice than for vehicle control mice (Fig. 3C). These results show that S14G-HN-treated male mice stayed close to the platform location longer than vehicle control mice, suggesting better cognitive and memory function of S14G-HN-treated mice than control. We also measured the duration that mice spent in the platform location (Fig. 3D). In the first 30 sec of probe test, S14G-HN-treated male mice stayed in the platform area significantly longer than control male mice. S14G-HN treated female mice showed a trend similar to the male mice, though the difference was not significant (Fig. 3B–D). Swimming speeds of S14G-HN treated and control mice were virtually the same in probe test (data not shown), indicating that locomotion activity was not affected by S14G-HN.

Bottom Line: We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains.NEP activity was also elevated by S14G-HN treatment in vitro.Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. tniikura@sfu.ca

ABSTRACT
Humanin (HN), a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD)-related cytotoxicities, including exposure to amyloid beta (Abeta), in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APP(swe), tau(P310L), and PS-1(M146V) that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G-HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD.

Show MeSH
Related in: MedlinePlus