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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 locomotor activity of 3xTg-AD mice.Male and female 3xTg-AD mice were subjected to behavioral analyses, Open field test (A–C) and Novel object recognition task (D), after 3 months intranasal administration of S14G-HN or vehicle. In Open field test, walking distance (A), walking speed (B) and duration stayed in the peripheral region (C) were measured. No significant difference was observed between S14G-HN and vehicle-treated mice in both genders. In Novel object recognition task, time of sniffing behavior to two objects was measured. In the first trial, no preference was observed in sniffing time of two objects (data not shown). The discrimination ratio in the second trial is shown (D). Bars indicate median, and p =  indicates p value of Mann-Whitney U test. Number of animals are male vehicle control: n = 7, S14G-HN: n = 9, female vehicle control: n = 8, S14G-HN: n = 7.
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pone-0016259-g002: The effect of S14G-HN on locomotor activity of 3xTg-AD mice.Male and female 3xTg-AD mice were subjected to behavioral analyses, Open field test (A–C) and Novel object recognition task (D), after 3 months intranasal administration of S14G-HN or vehicle. In Open field test, walking distance (A), walking speed (B) and duration stayed in the peripheral region (C) were measured. No significant difference was observed between S14G-HN and vehicle-treated mice in both genders. In Novel object recognition task, time of sniffing behavior to two objects was measured. In the first trial, no preference was observed in sniffing time of two objects (data not shown). The discrimination ratio in the second trial is shown (D). Bars indicate median, and p =  indicates p value of Mann-Whitney U test. Number of animals are male vehicle control: n = 7, S14G-HN: n = 9, female vehicle control: n = 8, S14G-HN: n = 7.

Mentions: To examine the effect of HN, we designed a 3-month treatment study using male and female 3xTg-AD mice (n = 9 in each group) at the early plaque-bearing stage. Since the progression of Abeta pathology in our colony is slower than that in the original colony [37], we started the treatment of mice at the age of 13 months (13.2±0.6). S14G-HN showed complete neuroprotective activity at 1nM of concentration in vitro [1], [6]. To achieve approximately 1nM of concentration in CNS, we chose a dose of S14G-HN at 10 nmol/day, based on the finding that intranasal administration of 5 nmol [125I]-IGF-I resulted in 0.32–1.44 nM of concentration in CNS region [51]. We treated male and female 3xTg-AD mice intranasally for three months with 10 nmol S14G-HN. After three months of treatment, we performed behavioral tests. In the Open Field test (Fig. 2A–C), no significant difference was observed between the vehicle and S14G-HN treated mice in total moving distance (Fig.2A), walking speed (Fig.2B), and time spent in peripheral area (Fig.2C). These results indicate that S14G-HN did not affect anxiety-induced locomotor activity and exploratory behaviors. In the Novel object recognition test (Fig. 2D), S14G-HN treated mice showed a trend toward improved recognition, though not reaching statistical significance.


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 locomotor activity of 3xTg-AD mice.Male and female 3xTg-AD mice were subjected to behavioral analyses, Open field test (A–C) and Novel object recognition task (D), after 3 months intranasal administration of S14G-HN or vehicle. In Open field test, walking distance (A), walking speed (B) and duration stayed in the peripheral region (C) were measured. No significant difference was observed between S14G-HN and vehicle-treated mice in both genders. In Novel object recognition task, time of sniffing behavior to two objects was measured. In the first trial, no preference was observed in sniffing time of two objects (data not shown). The discrimination ratio in the second trial is shown (D). Bars indicate median, and p =  indicates p value of Mann-Whitney U test. Number of animals are male vehicle control: n = 7, S14G-HN: n = 9, female vehicle control: n = 8, S14G-HN: n = 7.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3022031&req=5

pone-0016259-g002: The effect of S14G-HN on locomotor activity of 3xTg-AD mice.Male and female 3xTg-AD mice were subjected to behavioral analyses, Open field test (A–C) and Novel object recognition task (D), after 3 months intranasal administration of S14G-HN or vehicle. In Open field test, walking distance (A), walking speed (B) and duration stayed in the peripheral region (C) were measured. No significant difference was observed between S14G-HN and vehicle-treated mice in both genders. In Novel object recognition task, time of sniffing behavior to two objects was measured. In the first trial, no preference was observed in sniffing time of two objects (data not shown). The discrimination ratio in the second trial is shown (D). Bars indicate median, and p =  indicates p value of Mann-Whitney U test. Number of animals are male vehicle control: n = 7, S14G-HN: n = 9, female vehicle control: n = 8, S14G-HN: n = 7.
Mentions: To examine the effect of HN, we designed a 3-month treatment study using male and female 3xTg-AD mice (n = 9 in each group) at the early plaque-bearing stage. Since the progression of Abeta pathology in our colony is slower than that in the original colony [37], we started the treatment of mice at the age of 13 months (13.2±0.6). S14G-HN showed complete neuroprotective activity at 1nM of concentration in vitro [1], [6]. To achieve approximately 1nM of concentration in CNS, we chose a dose of S14G-HN at 10 nmol/day, based on the finding that intranasal administration of 5 nmol [125I]-IGF-I resulted in 0.32–1.44 nM of concentration in CNS region [51]. We treated male and female 3xTg-AD mice intranasally for three months with 10 nmol S14G-HN. After three months of treatment, we performed behavioral tests. In the Open Field test (Fig. 2A–C), no significant difference was observed between the vehicle and S14G-HN treated mice in total moving distance (Fig.2A), walking speed (Fig.2B), and time spent in peripheral area (Fig.2C). These results indicate that S14G-HN did not affect anxiety-induced locomotor activity and exploratory behaviors. In the Novel object recognition test (Fig. 2D), S14G-HN treated mice showed a trend toward improved recognition, though not reaching statistical significance.

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