Lysine-targeting inhibition of amyloid β oligomerization by a green perilla-derived metastable chalcone in vitro and in vivo.
Lysine-targeting inhibition of amyloid β oligomerization by a green perilla-derived metastable chalcone in vitro and in vivo.
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DOI：
10.1039/d2cb00194b
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发表时间：
2022-11-30
影响因子：
4.1
通讯作者：
Irie, Kazuhiro
中科院分区：
文献类型：
--
作者：
Murakami, Kazuma;Sakaguchi, Yoshiki;Taniwa, Kota;Izuo, Naotaka;Hanaki, Mizuho;Kawase, Taiji;Hirose, Kenji;Shimizu, Takahiko;Irie, Kazuhiro
β淀粉样蛋白（Aβ）寡聚体是阿尔茨海默病（AD）发病机制中的一种早期聚集形式，可引起神经毒性。因此，预防Aβ聚集对于预防AD是重要的。尽管对具有抗聚集特性的膳食化合物进行了深入研究，但一些已鉴定的化合物在水中孵育时易发生自氧化和/或水合作用，因此关于亚稳态化合物中的哪些活性结构实际上负责抑制Aβ聚集的问题尚未得到解答。本研究观察了紫苏衍生的绿色查尔酮2′，3 ′-二羟基-4 ′，6 ′-二甲氧基查尔酮（DDC）对42-mer Aβ（Aβ42）寡聚化的位点特异性抑制作用。DDC抑制Aβ42纤维化并减缓富含Aβ42聚集体的β折叠结构的转变。为了验证dDDC对DDC抑制Aβ42聚集的作用的贡献，我们合成了1-3，并鉴定了3，一种儿茶酚型黄酮，作为DDC的活性形式之一。1H-15 N SOFAST-HMQC NMR结果表明，1-3和DDC均能与分子间β折叠（Gln 15-Ala 21）附近的His 13和Leu 17之间的残基相互作用。Aβ42聚集体中的成核涉及低分子量寡聚体的限速形成。通过dDDC的自氧化，在二聚体的Lys 16和Lys 28处与dDDC形成席夫碱与Aβ42成核的抑制有关。值得注意的是，在使用免疫亲和纯化-质谱法的两种AD小鼠模型中，以与体外报告相似的方式观察到dDDC和脑Aβ之间的加合物形成。本研究结果揭示了亚稳态膳食成分对Aβ寡聚化的赖氨酸靶向抑制机制。我们提出紫苏衍生的绿色查耳酮DDC在体外和体内通过与水分子的亲核芳族取代转化为其分解的黄酮类化合物（1-3），对Aβ42寡聚化具有位点特异性抑制作用。
Oligomers of amyloid β (Aβ) represent an early aggregative form that causes neurotoxicity in the pathogenesis of Alzheimer's disease (AD). Thus, preventing Aβ aggregation is important for preventing AD. Despite intensive studies on dietary compounds with anti-aggregation properties, some identified compounds are susceptible to autoxidation and/or hydration upon incubation in water, leaving unanswered issues regarding which active structures in metastable compounds are actually responsible for the inhibition of Aβ aggregation. In this study, we observed the site-specific inhibition of 42-mer Aβ (Aβ42) oligomerization by the green perilla-derived chalcone 2′,3′-dihydroxy-4′,6′-dimethoxychalcone (DDC), which was converted to its decomposed flavonoids (dDDC, 1–3) via nucleophilic aromatic substitution with water molecules. DDC suppressed Aβ42 fibrillization and slowed the transformation of the β-sheet structure, which is rich in Aβ42 aggregates. To validate the contribution of dDDC to the inhibitory effects of DDC on Aβ42 aggregation, we synthesized 1–3 and identified 3, a catechol-type flavonoid, as one of the active forms of DDC. 1H–15N SOFAST-HMQC NMR revealed that 1–3 as well as DDC could interact with residues between His13 and Leu17, which were near the intermolecular β-sheet (Gln15–Ala21). The nucleation in Aβ42 aggregates involves the rate-limiting formation of low-molecular-weight oligomers. The formation of a Schiff base with dDDC at Lys16 and Lys28 in the dimer through autoxidation of dDDC was associated with the suppression of Aβ42 nucleation. Of note, in two AD mouse models using immunoaffinity purification-mass spectrometry, adduct formation between dDDC and brain Aβ was observed in a similar manner as reported in vitro. The present findings unraveled the lysine-targeting inhibitory mechanism of metastable dietary ingredients regarding Aβ oligomerization. We propose a site-specific inhibition of Aβ42 oligomerization by the green perilla-derived chalcone DDC, which is converted to its decomposed flavonoids (1–3) via nucleophilic aromatic substitution with water molecules, in vitro and in vivo.
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影响因子：
3.5
作者：
Hanaki, Mizuho;Murakami, Kazuma;Irie, Kazuhiro
通讯作者：
Irie, Kazuhiro
DOI：
10.3233/jad-179941
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
通讯作者：
Klein WL
影响因子：
14.9
作者：
Allen F;Pon A;Wilson M;Greiner R;Wishart D
通讯作者：
Wishart D
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
4.8
作者：
Ho, Lap;Ferruzzi, Mario G.;Pasinetti, Giulio Maria
通讯作者：
Pasinetti, Giulio Maria