ALZ-801 prevents amyloid β-protein assembly and reduces cytotoxicity: A preclinical experimental study

IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Daiki Muramatsu, Takahiro Watanabe-Nakayama, Mayumi Tsuji, Kenichi Umeda, Sadao Hikishima, Hiroto Nakano, Yasuhiro Sakashita, Tokuhei Ikeda, Hiroki Konno, Noriyuki Kodera, Toshio Ando, Moeko Noguchi-Shinohara, Kenjiro Ono
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引用次数: 0

Abstract

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, mainly characterized by amyloid β (Aβ) accumulation in the brain. Numerous new agents are currently undergoing clinical trials as disease-modifying therapies (DMTs) targeting Aβ. ALZ-801 is a promising candidate DMT for AD, with a phase 3 trial of ALZ-801 ongoing specifically for apolipoprotein E (APOE) ε4 homozygous patients with early-stage AD. This study aimed to examine the effects of ALZ-801 on Aβ assembly and explore its toxicological profile. Thioflavin T (ThT) assays and two imaging modalities—transmission electron microscopy (TEM) and high-speed atomic force microscopy (HS-AFM)—were used to evaluate ALZ-801's effects on Aβ assembly. To assess the effect of ALZ-801 on Aβ42-induced cytotoxicity, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and lactate dehydrogenase (LDH) assays were performed. ThT assays revealed increased lag time and decreased fluorescence in the presence of ALZ-801, confirming inhibition of Aβ42 fibril formation, as confirmed by TEM. Real-time observation using HS-AFM revealed that ALZ-801 inhibited the formation of Aβ42 fibril from low-molecular-weight (LMW)-Aβ42 in the presence of Aβ42 seeds. HS-AFM also revealed that globular aggregates from LMW-Aβ42 were significantly larger with ALZ-801, with few fibrils noted. MTT and LDH assays indicated that ALZ-801 prevented LMW-Aβ42-induced cytotoxicity but did not reduce cytotoxicity induced by high-molecular-weight-Aβ42. ALZ-801 can inhibit Aβ42 aggregation by preventing both nucleus formation and fibril elongation, while promoting large globular oligomer formation, and can significantly reduce LMW-Aβ42-induced cytotoxicity. These findings underscore the potential of ALZ-801 as an effective DMT for APOE ε4 homozygous patients with AD.

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来源期刊
The FASEB Journal
The FASEB Journal 生物-生化与分子生物学
CiteScore
9.20
自引率
2.10%
发文量
6243
审稿时长
3 months
期刊介绍: The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.
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