Mechanisms of Neuroprotection by a Novel Rescue Factor Humanin from Swedish Mutant Amyloid Precursor Protein

Hashimoto, Yuichi; Ito, Yuko; Niikura, Takako; Shao, Zongjun; Hata, Michihiro; Oyama, Fumitaka; Nishimoto, Ikuo

doi:10.1006/bbrc.2001.4765

Cited by 201 publications

(201 citation statements)

References 33 publications

(31 reference statements)

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“…Although it has been reported that iron mediates the neurotoxicity by A␤ peptides (Rottkamp et al, 2001), it is quite unlikely that HN and its active derivatives act as iron chelators, because of the following: (1) HN or HNG at Յ1 M had no action on A␤1-42 aggregation in vitro (data not shown), whereas A␤ aggregation is highly sensitive to redox-active metals, including iron (Jobling et al, 2001); and (2) HN and HNG had no inhibitory action against PrP106 -126 induced neurotoxicity, as shown in this study, whereas neurotoxicity by PrP106 -126 is abolished by chelation of redox-active metals (Jobling et al, 2001). In support of this notion, the presence of an HN action target other than A␤ is strongly indicated by the following observations: (3) HN and HNG were fully suppressive of neuronal death by anti-APP antibody, as shown in Figure 2, despite the fact that secreted A␤ does not mediate the neurotoxicity by anti-APP antibody (Sudo et al, 2001); and (4) HN and HNG can inhibit neuronal cell death by NL-APP mutant that cannot produce A␤1-42 (Hashimoto et al, 2001b). It is also stressed that the observed potency of R4A/ F6A-HNG, which exerts complete neuroprotection at 100 -300 pM, is remarkable.…”

Section: Discussionmentioning

confidence: 81%

Detailed Characterization of Neuroprotection by a Rescue Factor Humanin against Various Alzheimer's Disease-Relevant Insults

et al. 2001

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A novel factor, termed Humanin (HN), antagonizes against neurotoxicity by various types of familial Alzheimer's disease (AD) genes [V642I and K595N/M596L (NL) mutants of amyloid precursor protein (APP), M146L-presenilin (PS) 1, and N141I-PS2] and by A␤1-43 with clear action specificity ineffective on neurotoxicity by polyglutamine repeat Q79 or superoxide dismutase 1 mutants. Here we report that HN can also inhibit neurotoxicity by other AD-relevant insults: other familial AD genes (A617G-APP, L648P-APP, A246E-PS1, L286V-PS1, C410Y-PS1, and H163R-PS1), APP stimulation by anti-APP antibody, and other A␤ peptides (A␤1-42 and A␤25-35). The action specificity was further indicated by the finding that HN could not suppress neurotoxicity by glutamate or prion fragment. Against the AD-relevant insults, essential roles of Cys 8 and Ser 14 were commonly indicated, and the domain from Pro 3 to Pro 19 was responsible for the rescue action of HN, in which seven residues turned out to be essential. We also compared the neuroprotective action of S14G HN (HNG) with that of activity-dependent neurotrophic factor, IGF-I, or basic FGF for the antagonism against various AD-relevant insults (V642I-APP, NL-APP, M146L-PS1, N141I-PS2, and A␤1-43). Although all of these factors could abolish neurotoxicity by A␤1-43, only HNG could abolish cytotoxicities by all of them. HN and HN derivative peptides may provide a new insight into the study of AD pathophysiology and allow new avenues for the development of therapeutic interventions for various forms of AD.

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Section: Discussionmentioning

confidence: 81%

Detailed Characterization of Neuroprotection by a Rescue Factor Humanin against Various Alzheimer's Disease-Relevant Insults

et al. 2001

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“…HN is a small molecular-weight peptide that potently functions against AD-related insults by promoting cell survival in vitro [17] . Although the neuroprotective effects of HN are now well known [21,41] and have been confi rmed in transgenic AD mice [42] , the intrinsic mechanisms by which it suppresses AD-like pathological changes and memory deficits in vivo are still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Humanin (HN) is a 24-amino-acid peptide that was identified in the occipital lobe of AD brains [17] . HN suppresses the neurotoxicity of various causative genes for familial AD (FAD) including FAD-related mutant PS1 and PS2 genes [17][18][19] , and inhibits the neuronal cell death caused by Aβ [20,21] .…”

Section: Introductionmentioning

confidence: 99%

“…HN suppresses the neurotoxicity of various causative genes for familial AD (FAD) including FAD-related mutant PS1 and PS2 genes [17][18][19] , and inhibits the neuronal cell death caused by Aβ [20,21] . HN is also effective against cell death caused by non-AD-related insults, such as serum deprivation, prion peptide 118-135, and insulin-like growth factor binding protein 3 [22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

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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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“…ApoE4 is the established insults relevant to AD and causes apoptotic cell death, when F11 neurohybrid cells are treated with apoE4 (21). As shown in Fig.…”

Section: Hgtx Inhibits Cell Death By L648p-a␤pp and Low Expression Ofmentioning

confidence: 90%

The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

Hashimoto

Tsuji

Kanekura

et al. 2004

Journal of Biological Chemistry

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Mechanisms of Neuroprotection by a Novel Rescue Factor Humanin from Swedish Mutant Amyloid Precursor Protein

Cited by 201 publications

References 33 publications

Detailed Characterization of Neuroprotection by a Rescue Factor Humanin against Various Alzheimer's Disease-Relevant Insults

Detailed Characterization of Neuroprotection by a Rescue Factor Humanin against Various Alzheimer's Disease-Relevant Insults

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

The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

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