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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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Effect of S14G-HN on tau phosphorylation.A, B. Brain homogenate of 3xTg-AD mice treated with S14G-HN (H) or vehicle (V) was subjected to immunoblot analysis using anti-phosphorylated tau (Ser202) (AT8) (upper panel in A), anti-phosphorylated tau (Thr231) (AT180) (upper panel in B), anti-total tau (tau46) (middle panels) and anti-beta-actin (lower panels) antibodies. C–F. Brain sections were subjected to immunostaining using anti-phosphorylated tau (Ser202) (AT8) antibody (C, D) or anti-phosphorylated tau (Thr231) (AT180) antibody (E, F) and biotin-conjugated secondary antibody followed by visualization with ABC method. Representative images of hippocampal CA1 region of vehicle (C, E) and S14G-HN (D, F) treated mouse sections are shown. Bar  = 200 µm.
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pone-0016259-g007: Effect of S14G-HN on tau phosphorylation.A, B. Brain homogenate of 3xTg-AD mice treated with S14G-HN (H) or vehicle (V) was subjected to immunoblot analysis using anti-phosphorylated tau (Ser202) (AT8) (upper panel in A), anti-phosphorylated tau (Thr231) (AT180) (upper panel in B), anti-total tau (tau46) (middle panels) and anti-beta-actin (lower panels) antibodies. C–F. Brain sections were subjected to immunostaining using anti-phosphorylated tau (Ser202) (AT8) antibody (C, D) or anti-phosphorylated tau (Thr231) (AT180) antibody (E, F) and biotin-conjugated secondary antibody followed by visualization with ABC method. Representative images of hippocampal CA1 region of vehicle (C, E) and S14G-HN (D, F) treated mouse sections are shown. Bar  = 200 µm.

Mentions: A major characteristic of 3xTg-AD mice is age-dependent progression of tau pathology. We thus examined the effect of S14G-HN on tau pathology. Phosphorylation of tau protein was assessed by immunoblot using phosphorylation site-specific antibodies (AT8, AT180, and AT270 for Ser208, Thr231, and Thr181, respectively). Total tau was assessed by tau46 antibody. The level of total tau (normalized by actin) was not changed by S14G-HN (Fig. 7A,B). The relative intensity of bands in S14G-HN-treated mouse brain homogenate (percentage of corresponding vehicle control, mean±SD) was 100±21 (male) and 112±17 (female). The ratio of phosphorylated tau (Ser202) to total tau was not different between S14G-HN treated and control mice: the value of S14G-HN calculated as percentage of corresponding vehicle control (mean±SD) was 101±39 (male) and 95±23 (female). No significant difference between S14G-HN treated and control mice was detected in phosphorylation of Thr231 (Fig. 7B) and Thr181 (data not shown). Consistently, no difference was observed between vehicle and S14G-HN treated mouse brains by immunohistochemical analysis using anti-phosphorylated tau antibody AT8 (Fig. 7C, D) and AT180 (Fig.7E, F). Thus, S14G-HN showed no effect on tau pathology at least at the early plaque-bearing stage.


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)

Effect of S14G-HN on tau phosphorylation.A, B. Brain homogenate of 3xTg-AD mice treated with S14G-HN (H) or vehicle (V) was subjected to immunoblot analysis using anti-phosphorylated tau (Ser202) (AT8) (upper panel in A), anti-phosphorylated tau (Thr231) (AT180) (upper panel in B), anti-total tau (tau46) (middle panels) and anti-beta-actin (lower panels) antibodies. C–F. Brain sections were subjected to immunostaining using anti-phosphorylated tau (Ser202) (AT8) antibody (C, D) or anti-phosphorylated tau (Thr231) (AT180) antibody (E, F) and biotin-conjugated secondary antibody followed by visualization with ABC method. Representative images of hippocampal CA1 region of vehicle (C, E) and S14G-HN (D, F) treated mouse sections are shown. Bar  = 200 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3022031&req=5

pone-0016259-g007: Effect of S14G-HN on tau phosphorylation.A, B. Brain homogenate of 3xTg-AD mice treated with S14G-HN (H) or vehicle (V) was subjected to immunoblot analysis using anti-phosphorylated tau (Ser202) (AT8) (upper panel in A), anti-phosphorylated tau (Thr231) (AT180) (upper panel in B), anti-total tau (tau46) (middle panels) and anti-beta-actin (lower panels) antibodies. C–F. Brain sections were subjected to immunostaining using anti-phosphorylated tau (Ser202) (AT8) antibody (C, D) or anti-phosphorylated tau (Thr231) (AT180) antibody (E, F) and biotin-conjugated secondary antibody followed by visualization with ABC method. Representative images of hippocampal CA1 region of vehicle (C, E) and S14G-HN (D, F) treated mouse sections are shown. Bar  = 200 µm.
Mentions: A major characteristic of 3xTg-AD mice is age-dependent progression of tau pathology. We thus examined the effect of S14G-HN on tau pathology. Phosphorylation of tau protein was assessed by immunoblot using phosphorylation site-specific antibodies (AT8, AT180, and AT270 for Ser208, Thr231, and Thr181, respectively). Total tau was assessed by tau46 antibody. The level of total tau (normalized by actin) was not changed by S14G-HN (Fig. 7A,B). The relative intensity of bands in S14G-HN-treated mouse brain homogenate (percentage of corresponding vehicle control, mean±SD) was 100±21 (male) and 112±17 (female). The ratio of phosphorylated tau (Ser202) to total tau was not different between S14G-HN treated and control mice: the value of S14G-HN calculated as percentage of corresponding vehicle control (mean±SD) was 101±39 (male) and 95±23 (female). No significant difference between S14G-HN treated and control mice was detected in phosphorylation of Thr231 (Fig. 7B) and Thr181 (data not shown). Consistently, no difference was observed between vehicle and S14G-HN treated mouse brains by immunohistochemical analysis using anti-phosphorylated tau antibody AT8 (Fig. 7C, D) and AT180 (Fig.7E, F). Thus, S14G-HN showed no effect on tau pathology at least at the early plaque-bearing stage.

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