Publications by authors named "Yumi Irie"
Since amyloid β (Aβ) oligomers are more cytotoxic than fibrils, various dimer models have been synthesized. We focused on the C-terminal region that could form a hydrophobic core in the aggregation process and identified a toxic conformer-restricted dimer model (E22P,G38DAP-Aβ40 dimer) with an l,l-2,6-diaminopimelic acid linker ( = 3) at position 38, which exhibited moderate cytotoxicity. We synthesized four additional linkers ( = 2, 4, 5, 7) to determine the most appropriate distance between the two Aβ40 monomers for a toxic dimer model.
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- Oligomers of the amyloid β (Aβ) protein are key players in Alzheimer's disease, but their variable structures and instability make it hard to understand how they work and their toxicity levels.
- Researchers have created new trimer models of Aβ with different linkers to test their cytotoxic effects, finding that some models mimic toxic structures better than others.
- The most effective trimer models showed significant cytotoxicity and ability to form protofibrils, indicating that the arrangement and behavior of these oligomers, rather than just their stability, are critical in their toxic effects.
Structural basis of the 24B3 antibody against the toxic conformer of amyloid β with a turn at positions 22 and 23.
Biochem Biophys Res Commun
September 2022
Amyloid β-protein (Aβ) oligomers are involved in the early stages of Alzheimer's disease (AD) and antibodies against these toxic oligomers could be useful for accurate diagnosis of AD. We identified the toxic conformer of Aβ42 with a turn at positions 22/23, which has a propensity to form toxic oligomers. The antibody 24B3, developed by immunization of a toxic conformer surrogate E22P-Aβ9-35 in mice, was found to be useful for AD diagnosis using human cerebrospinal fluid (CSF).
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- Amyloid β (Aβ) oligomers are crucial in causing Alzheimer's disease, with a focus on a specific form of Aβ42 that has a unique disulfide bond structure.
- Researchers created three modified versions of Aβ42, using different combinations of cysteine and homocysteine, and found that most of these variants were highly toxic to specific cell lines, while one variant was not.
- The study revealed that the toxic effects were tied more to the specific shape (conformation) of Aβ42 than to its clustering into larger oligomers, as shown by various experimental methods.
Article Synopsis
- The study focuses on the characteristics of amyloid β (Aβ) oligomers, which are toxic species involved in Alzheimer's disease (AD) but are difficult to analyze due to their instability.
- Researchers developed a modified version of Aβ42 (SS-Aβ42) that forms stable oligomers and proved to be more cytotoxic in cell cultures than its wild-type counterpart and a more aggregative mutant.
- An antibody, TxCo-1, was created to specifically target the toxic form of SS-Aβ42, and its use revealed that this oligomeric form is associated with brain structures in Alzheimer’s patients, providing insights into its role in AD pathology.
Article Synopsis
- Researchers have synthesized quasi-stable trimer models of the Aβ40 protein with potentially toxic conformations using a specific linker at various positions.
- Out of the synthesized trimers, only the one linked at position 38 showed weak neurotoxicity against SH-SY5Y cells.
- This finding indicates that the trimer model may be less likely to form toxic oligomers compared to the corresponding dimer model.
Amyloid β (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease. Nevertheless, its distribution and clearance before Aβ plaque formation needs to be elucidated. Using an optimized immunofluorescent staining method, we examined the distribution of Aβ in the post-mortem parietal cortex of 35 subjects, 30 to 65 years of age, APOE ε3/ε3, without AD lesions.
View Article and Find Full Text PDFThe formation of soluble oligomers of amyloid β42 and 40 (Aβ42, Aβ40) is the initial event in the pathogenesis of Alzheimer's disease (AD). Based on previous systematic proline replacement and solid-state NMR, we proposed a toxic dimer structure of Aβ42, a highly aggregative alloform, with a turn at positions 22 and 23, and a hydrophobic core in the C-terminal region. However, in addition to Aβ42, Aβ40 dimers can also contribute to AD progression because of the more abundance of Aβ40 monomer in biological fluids.
View Article and Find Full Text PDFAmyloid β-protein (Aβ42) oligomerization is an early event in Alzheimer's disease (AD). Current diagnostic methods using sequence-specific antibodies against less toxic fibrillar and monomeric Aβ42 run the risk of overdiagnosis. Hence, conformation-specific antibodies against neurotoxic Aβ42 oligomers have garnered much attention for developing more accurate diagnostics.
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