Non-toxic conformer of amyloid β may suppress amyloid β-induced toxicity in rat primary neurons: Implications for a novel therapeutic strategy for Alzheimer’s disease

Izuo, Naotaka; Murakami, Kazuma; Satô, Mizuho; Iwasaki, Mami; Izumi, Yasukatsu; Shimizu, Takahiko; Akaike, Akinori; Irie, Kazuhiro; Kume, Toshiaki

doi:10.1016/j.bbrc.2013.05.106

Cited by 17 publications

(10 citation statements)

References 19 publications

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“…This mutation rapidly accelerates aggregation and results in enhanced toxicity and altered pathology ( 27 ). Conversely, other mutations within the turn region (G25P and E22V) have been shown to form non-toxic oligomers ( 57 ). Moreover, phosphorylation of Ser 26 in the turn region of Aβ destabilizes the hairpin conformation ( 23 ), whereas constraint of Asp 23 and Lys 28 by a lactam bridge stabilizes the hairpin and enhances the aggregation rate ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Comparisons with Amyloid-β Reveal an Aspartate Residue That Stabilizes Fibrils of the Aortic Amyloid Peptide Medin

Davies

Madine

Middleton

2015

Journal of Biological Chemistry

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Background: Aggregates of the 50-aa protein medin are the main constituent of aortic medial amyloid.Results: Medin aggregation involves an aspartate residue analogous to Asp23 of the Alzheimer Aβ peptide.Conclusion: There are striking similarities in the aggregation properties of medin and Aβ.Significance: Mechanistic insights will assist future investigations of medin in the most common form of human amyloid.

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Section: Discussionmentioning

confidence: 99%

Comparisons with Amyloid-β Reveal an Aspartate Residue That Stabilizes Fibrils of the Aortic Amyloid Peptide Medin

Davies

Madine

Middleton

2015

Journal of Biological Chemistry

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“…Similar results were obtained in the test using rat primary neurons. 113) The following dot blotting study of Aβ42 demonstrated the gradual increase of 11A1 reactivity in a time-dependent manner, which preceded neurotoxicity. 114) On the other hand, the immunoreactivity of Aβ42 by other sequence-specific antibodies remained constant.…”

Section: A1 Antibodymentioning

confidence: 95%

Conformation-specific antibodies to target amyloid β oligomers and their application to immunotherapy for Alzheimer’s disease

Murakami

2014

Bioscience, Biotechnology, and Biochemistry

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Amyloid β-protein (Aβ) oligomers, intermediates of Aβ aggregation, cause cognitive impairment and synaptotoxicity in the pathogenesis of Alzheimer's disease (AD). Immunotherapy using anti-Aβ antibody is one of the most promising approaches for AD treatment. However, most clinical trials using conventional sequence-specific antibodies have proceeded with difficulty. This is probably due to the unintended removal of the non-pathological monomer and fibrils of Aβ as well as the pathological oligomers by these antibodies that recognize Aβ sequence, which is not involved in synaptotoxicity. Several efforts have been made recently to develop conformation-specific antibodies that target the tertiary structure of Aβ oligomers. Here, we review the recent findings of Aβ oligomers and anti-Aβ antibodies including our own, and discuss their potential as therapeutic and diagnostic tools.

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“…This experiment was performed as described previously [30][31][32] with some modifications. Briefly, using a narrow-mouth pipette tip, the ileal membrane fractions suspended in chilled Tris buffer containing 20 mM Tris-HCl (pH 7.4), 2 mM ethylenediamine tetraacetic acid and 0.5 mM ethylene glycol tetraacetic acid (0.10 µg total protein dose in 2 µL) were spotted slowly onto the nitrocellulose membrane at the center of each grid drawn by pencil.…”

Section: Dot Blot Analysismentioning

confidence: 99%

Changes in PtdIns(4,5)P2 Induced by Etoposide Treatment Modulates Small Intestinal P-Glycoprotein <i>via</i> Radixin

Kobori

Harada

Nakamoto

et al. 2014

Biological & Pharmaceutical Bulletin

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Previously, we reported that repeated oral administration of etoposide (ETP) increases P-glycoprotein (P-gp) expression in association with activation of ezrin/radixin/moesin (ERM) via Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil containing protein kinase (ROCK) signaling in the small intestine. However, the detailed mechanisms of this pathway have yet to be fully elucidated. Recently, phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], one of the most abundant phosphoinositides in the plasma membrane, has attracted attention regarding its involvement in the plasma membrane localization of various membrane proteins. PtdIns(4,5)P2 is an essential factor in the dissociation and subsequent membrane translocation (activation) of ERM, and its synthetic pathway is known to be highly regulated by RhoA/ROCK signaling. Here, we examined the involvement of PtdIns(4,5)P2 in the mechanism by which ETP treatment increases small intestinal P-gp levels, and we determined which protein within ERM contributes to this phenomenon. Key words P-glycoprotein; radixin; phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2); Ras homolog gene family member A (RhoA); Rho-associated coiled-coil containing protein kinase (ROCK); small intestine We previously reported that repeated oral treatment with etoposide (ETP), an anticancer drug that is a substrate for Pglycoprotein (P-gp), 1) activates ezrin/radixin/moesin (ERM), which are scaffold proteins for P-gp in the small intestine. 2,3)Activated ERM may in turn increase P-gp expression in the plasma membrane of the small intestine under ETP treatment.2,3) ERM activation is regulated by Ras homolog gene family member A (RhoA) and Rho-associated coiled-coil containing protein kinase (ROCK) signaling, as demonstrated in our previous studies 2,3) and others. 4,5) In our reports we proposed the possibility that of the ERM proteins, radixin may contribute to the above phenomena more than ezrin or moesin 6)

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Non-toxic conformer of amyloid β may suppress amyloid β-induced toxicity in rat primary neurons: Implications for a novel therapeutic strategy for Alzheimer’s disease

Cited by 17 publications

References 19 publications

Comparisons with Amyloid-β Reveal an Aspartate Residue That Stabilizes Fibrils of the Aortic Amyloid Peptide Medin

Comparisons with Amyloid-β Reveal an Aspartate Residue That Stabilizes Fibrils of the Aortic Amyloid Peptide Medin

Conformation-specific antibodies to target amyloid β oligomers and their application to immunotherapy for Alzheimer’s disease

Changes in PtdIns(4,5)P2 Induced by Etoposide Treatment Modulates Small Intestinal P-Glycoprotein <i>via</i> Radixin

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