Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection

Hashimoto, Yuichi; Suzuki, Hiroaki; Aiso, Sadakazu; Niikura, Takako; Nishimoto, Ikuo; Matsuoka, Masao

doi:10.1016/j.lfs.2005.03.031

Cited by 96 publications

(105 citation statements)

References 31 publications

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“…Our recent studies have demonstrated that HN signals against ADrelevant neuronal death are intracellularly mediated by STAT3 in vitro Hashimoto et al, 2005). Earlier studies established the therapeutic effect of HN derivatives on functional memory deficits caused by AD-relevant insults, such as cholinotoxins and soluble Ab (Mamiya and Ukai, 2001;Krejcova et al, 2004;Chiba et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…administered with CLN, ADNF, or AGA-(C8R)HNG17 because it has been shown that STAT3 is an essential effecter for intracellular signals activated by HN and its derivatives in vitro Hashimoto et al, 2005;Matsuoka et al, 2006). Short-term i.n.…”

Section: Stat3 Is Involved In Cln-mediated Inhibition Of Cholinotoxinmentioning

confidence: 99%

“…Colivelin (CLN), the strongest HN derivative so far developed, is a fusion peptide composed of a potent HN derivative named AGA-(C8R)HNG17 attached to the C terminus of activitydependent neurotrophic factor (ADNF) (Brenneman and Gozes, 1996;Brenneman et al, 1998;Chiba et al, 2004Chiba et al, , 2005Chiba et al, , 2006Matsuoka et al, 2006). Our earlier studies indicated that HN and CLN suppressed AD-relevant neuronal death by activating STAT3 in vitro Hashimoto et al, 2005;Matsuoka et al, 2006). It has been also demonstrated in vivo that HN derivatives, including CLN, suppress spatial working memory impairment induced by blockers to the cholinergic system or intracerebroventricular (i.c.v.)…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

Yamada

Chiba

Sasabe

et al. 2007

Neuropsychopharmacol

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Humanin (HN) and its derivatives, such as Colivelin (CLN), suppress neuronal death induced by insults related to Alzheimer's disease (AD) by activating STAT3 in vitro. They also ameliorate functional memory impairment of mice induced by anticholinergic drugs or soluble toxic amyloid-b (Ab) in vivo when either is directly administered into the cerebral ventricle or intraperitoneally injected. However, the mechanism underlying the in vivo effect remains uncharacterized. In addition, from the standpoint of clinical application, drug delivery methods that are less invasive and specific to the central nervous system (CNS) should be developed. In this study, we show that intranasally (i.n.) administered CLN can be successfully transferred to CNS via the olfactory bulb. Using several behavioral tests, we have demonstrated that i.n. administered CLN ameliorates memory impairment of AD models in a dose-responsive manner. Attenuation of AD-related memory impairment by HN derivatives such as CLN appears to be correlated with an increase in STAT3 phosphorylation levels in the septohippocampal region, suggesting that anti-AD activities of HN derivatives may be mediated by activation of STAT3 in vivo as they are in vitro. We further demonstrate that CLN treatment inhibits an Ab induced decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Combined with the finding that HN derivatives upregulate mRNA expression of neuronal ChAT and vesicular acetylcholine transporter (VAChT) in vitro, it is assumed that CLN may ameliorate memory impairment of AD models by supporting cholinergic neurotransmission, which is at least partly mediated by STAT3-mediated transcriptional upregulation of ChAT and VAChT.

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Section: Discussionmentioning

confidence: 99%

Section: Stat3 Is Involved In Cln-mediated Inhibition Of Cholinotoxinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

Yamada

Chiba

Sasabe

et al. 2007

Neuropsychopharmacol

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“…The loss-of-function of any of the htHNR subunits abolishes Humanin-induced inhibition of ADrelated neuronal death (31,32). The binding of Humanin to htHNR results in oligomerization of the receptor subunits and the activation of JAK2 and STAT3 (22,(31)(32)(33), which is thought to alter expression of target genes of Humanin. However, it remains unknown which target genes of Humanin mediates the neuroprotective effect of Humanin.…”

Section: Humanin Is a Secreted Bioactive Peptide That Suppresses Cellmentioning

confidence: 99%

SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

Takeshita

Hashimoto

Nawa

et al. 2013

Journal of Biological Chemistry

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Background: Humanin, a secreted bioactive peptide, suppresses a variety of cell toxicities. Results: An intracellular protein SH3BP5, which directly inhibits JNK activity, is identified as an effector of Humanin. Conclusion: SH3BP5 is a physiological inhibitor of JNK and the firstly identified effector of Humanin. Significance: The discovery provides a novel mechanistic insight into the actions of JNK and Humanin.

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“…it protects cerebrovascular smooth muscle cells from Aβ-induced toxicity [50] , and HN or HN-like peptides such as rattin, a rat homologue of HN, are protective against serum withdrawal [51] and N-methyl-D-aspartate-induced excitotoxicity in primary cortical neuronal and glial cocultures [52] . HN negates Aβ-induced neuronal death in vitro [50] .…”

Section: Discussionmentioning

confidence: 99%

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

Chai

Duan

et al. 2014

Neurosci. Bull.

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Amyloid β-peptide (Aβ) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Humanin (HN) is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism(s) by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study, we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre-and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ 1-42 . HN also attenuated Aβ 1-42 -induced tau hyperphosphorylation, apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A (PP2A) catalytic subunit and thereby activating PP2A. HN also inhibited apoptosis and reduced the oxidative stress induced by Aβ 1-42 . These fi ndings provide novel mechanisms of action for the ability of HN to protect against Aβ 1-42 -induced AD-like pathological changes and memory defi cits.

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Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection

Cited by 96 publications

References 31 publications

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

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