Secreted Aβ Does Not Mediate Neurotoxicity by Antibody-Stimulated Amyloid Precursor Protein

Sudo, Haruka; Hashimoto, Yuichi; Niikura, Takako; Shao, Zongjun; Yasukawa, Takashi; Ito, Yuko; Yamada, Marina; Hata, Michihiro; Hiraki, Takako; Kawasumi, Masaoki; Kouyama, Keisuke; Nishimoto, Ikuo

doi:10.1006/bbrc.2001.4604

Cited by 33 publications

(67 citation statements)

References 39 publications

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“…As Rohn et al (2000) and Sudo et al (2000Sudo et al ( , 2001 reported independently, treatment of primary neurons with anti-APP antibody 22C11 resulted in significantly increased cell death (Fig. 2).…”

Section: Effect Of Shn and Its Derivatives On Neuronal Death By Anti-supporting

confidence: 67%

“…As reported in previous studies (Yankner et al, 1990;Loo et al, 1993;Pike et al, 1993;Gschwind and Huber, 1995;Kaneko et al, 1995;Giovanni et al, 1999;Sudo et al, 2001), Ն10 M A␤1-42 causes massive cell death in neurons. Although we identified previously the protective effects of HN and S14G HN (HNG) against neurotoxicity by A␤1-43 (Hashimoto et al, 2001a(Hashimoto et al, ., 1994Mann et al, 1996) and because it is believed that A␤42 neurotoxicity contributes to the pathogenesis of AD, we emphasize that there is no evidence showing that there is a difference between neurotoxicity by A␤1-42 and A␤1-43.…”

Section: Effect Of Shn and Its Derivatives On A␤1-42-induced Neuronalsupporting

confidence: 62%

“…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: 70%

“…Other mutant PS1 cDNAs were provided by Dr. Peter St. George-Hyslop (University of Toronto, Toronto, C anada) and used after being subcloned to pcDNA. A617G-APP and L648P-APP cDNAs were constructed from wtAPP 695 (Sudo et al, 2001) using a kit (C lontech, Palo Alto, CA) and inserted to pcDNA. HN peptides were chemically synthesized and purified to Ͼ95% purity (Peptide Institute, Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…FAD mutant PS1 enhances death in PC12 cells (Guo et al, 1996;Weihl et al, 1999) and primary neurons (Czech et al, 1998;Zhang et al, 1998;Guo et al, 1999;Weihl et al, 1999). Rohn et al (2000) and Sudo et al (2000Sudo et al ( , 2001 independently found that treatment of neuronal cells with anti-APP antibody remarkably enhances the neurotoxic function of wild-type (wt) APP, whose overexpression could cause AD type of neurodegeneration in Down's syndrome. Therefore, an important clue in the development of AD therapy would be provided by finding the molecules that suppress neuronal cell death by these AD-relevant insults.…”

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confidence: 99%

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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: Effect Of Shn and Its Derivatives On Neuronal Death By Anti-supporting

confidence: 67%

Section: Effect Of Shn and Its Derivatives On A␤1-42-induced Neuronalsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2001

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Death and survival of neuronal cells exposed to Alzheimer's insults

Niikura

Hashimoto

Tajima

et al. 2002

J of Neuroscience Research

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Neuronal cell death is the central abnormality occurring in brains suffering from Alzheimer's disease (AD). The notion that AD is a disease caused by loss of neurons points toward suppression of neuronal death as the most important therapeutic target. Nevertheless, the mechanisms for neuronal death in AD are still relatively unclear. Three known mutant genes cause familial AD (FAD): amyloid precursor protein, presenilin 1, and presenilin 2. Detailed analysis of cytotoxic mechanisms of the FADlinked mutant genes reveals that they cause neuronal cell death at physiologically low expression levels. Unexpectedly, cytotoxic mechanisms vary depending on the type of mutations and genes, suggesting that various mechanisms for neuronal cell death are involved in AD patients. In support of this, activity-dependent neurotrophic factor, basic fibroblast growth factor, and insulin-like growth factor-I can completely protect neurons from ␤-amyloid (A␤) cytotoxicity but exhibit incomplete or little effect on cytotoxicity by FAD mutant genes. By contrast, Humanin, a newly identified 24-residue peptide, suppresses neuronal cell death by various FAD mutants and A␤, whereas this factor has no effect on cytotoxicity from AD-irrelevant insults. Studies investigating death and survival of neuronal cells exposed to AD insults will open a new horizon in developing therapy aimed at neuroprotection.

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Characterization of the toxic mechanism triggered by Alzheimer's amyloid‐β peptides via p75 neurotrophin receptor in neuronal hybrid cells

Tsukamoto

Hashimoto

Kanekura

et al. 2003

J of Neuroscience Research

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Neuronal pathology of the brain with Alzheimer's disease (AD) is characterized by numerous depositions of amyloid-beta peptides (Abeta). Abeta binding to the 75-kDa neurotrophin receptor (p75NTR) causes neuronal cell death. Here we report that Abeta causes cell death in neuronal hybrid cells transfected with p75NTR, but not in nontransfected cells, and that p75NTR(L401K) cannot mediate Abeta neurotoxicity. We analyzed the cytotoxic pathway by transfecting pertussis toxin (PTX)-resistant G protein alpha subunits in the presence of PTX and identified that Galpha(o), but not Galpha(i), proteins are involved in p75NTR-mediated Abeta neurotoxicity. Further investigation suggested that Abeta neurotoxicity via p75NTR involved JNK, NADPH oxidase, and caspases-9/3 and was inhibited by activity-dependent neurotrophic factor, insulin-like growth factor-I, basic fibroblast growth factor, and Humanin, as observed in primary neuron cultures. Understanding the Abeta neurotoxic mechanism would contribute significantly to the development of anti-AD therapies.

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Secreted Aβ Does Not Mediate Neurotoxicity by Antibody-Stimulated Amyloid Precursor Protein

Cited by 33 publications

References 39 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

Death and survival of neuronal cells exposed to Alzheimer's insults

Characterization of the toxic mechanism triggered by Alzheimer's amyloid‐β peptides via p75 neurotrophin receptor in neuronal hybrid cells

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