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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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Related in: MedlinePlus

S14G-HN does not affect APP production and processing.Brain homogenate of 3xTg-AD mice treated with S14G-HN (HNG or H) or vehicle (veh or V) was subjected to immunoblot analysis using anti-APP C-terminus (A) or anti-sAPPalpha (B) (upper panels) and anti-beta-actin (lower panels) antibodies.
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pone-0016259-g005: S14G-HN does not affect APP production and processing.Brain homogenate of 3xTg-AD mice treated with S14G-HN (HNG or H) or vehicle (veh or V) was subjected to immunoblot analysis using anti-APP C-terminus (A) or anti-sAPPalpha (B) (upper panels) and anti-beta-actin (lower panels) antibodies.

Mentions: To understand how S14G-HN suppresses Abeta accumulation, we next examined the levels of full-length APP and sAPPalpha, a cleaved product of alpha-secretase. We performed immunoblot analysis of brain homogenate using antibodies that specifically recognize C-terminal regions of APP and sAPPalpha, respectively (Fig. 5). Quantitative analysis showed no significant difference in levels of full-length APP and sAPPalpha between S14G-HN and vehicle treated mice (number of animals; vehicle male = 7, female = 9, S14G-HN male = 9, female = 7): relative intensity of full-length APP and sAPPalpha bands in S14G-HN-treated brain homogenate (indicated as percentage of corresponding vehicle control, mean±SD) was 98±17 (male), 106±15 (female) and 81±15 (male), 98±16 (female), respectively. In addition, we detected no difference in sAPPbeta level between S14G-HN and vehicle control (data not shown). These results suggest that S14G-HN altered neither APP production nor processing by secretases.


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)

S14G-HN does not affect APP production and processing.Brain homogenate of 3xTg-AD mice treated with S14G-HN (HNG or H) or vehicle (veh or V) was subjected to immunoblot analysis using anti-APP C-terminus (A) or anti-sAPPalpha (B) (upper panels) and anti-beta-actin (lower panels) antibodies.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0016259-g005: S14G-HN does not affect APP production and processing.Brain homogenate of 3xTg-AD mice treated with S14G-HN (HNG or H) or vehicle (veh or V) was subjected to immunoblot analysis using anti-APP C-terminus (A) or anti-sAPPalpha (B) (upper panels) and anti-beta-actin (lower panels) antibodies.
Mentions: To understand how S14G-HN suppresses Abeta accumulation, we next examined the levels of full-length APP and sAPPalpha, a cleaved product of alpha-secretase. We performed immunoblot analysis of brain homogenate using antibodies that specifically recognize C-terminal regions of APP and sAPPalpha, respectively (Fig. 5). Quantitative analysis showed no significant difference in levels of full-length APP and sAPPalpha between S14G-HN and vehicle treated mice (number of animals; vehicle male = 7, female = 9, S14G-HN male = 9, female = 7): relative intensity of full-length APP and sAPPalpha bands in S14G-HN-treated brain homogenate (indicated as percentage of corresponding vehicle control, mean±SD) was 98±17 (male), 106±15 (female) and 81±15 (male), 98±16 (female), respectively. In addition, we detected no difference in sAPPbeta level between S14G-HN and vehicle control (data not shown). These results suggest that S14G-HN altered neither APP production nor processing by secretases.

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