School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
Zibo City Engineering Research Center for New Pollution Monitoring and Governance, Shandong Vocational College of Light Industry, Zibo, Shandong 255300, China.
ACS Chem Neurosci. 2024 Nov 20;15(22):4220-4228. doi: 10.1021/acschemneuro.4c00509. Epub 2024 Nov 4.
Aβ42 aggregation was implicated in the pathogenesis of Alzheimer's disease (AD) without effective treatment available currently. Future efforts in clinical trials should instead focus on applying those antiamyloid treatment strategies to the preclinical stage and "the earlier, the better". How to identify and inhibit Aβ42 oligomers in the different stages of aggregation is therefore becoming the key to controlling primary aggregation and consequent AD development. Aggregation-induced emission probe DNTPH was demonstrated recently, enabling detection of amyloid at wavelengths up to 710 nm and exhibiting strong inhibitory effects on Aβ fibrosis at low dose. However, the detection and inhibition mechanisms of Aβ oligomers at various early stages of aggregation remain unknown. To this end, we built four different morphologies of Aβ42 pentamers characterized by products in monomeric aggregate (P), primary nucleation (P), secondary nucleation (P), and fibril stages (P) to explore the distinguishable ability and inhibition mechanisms of DNTPH with different concentrations upon binding. The results showcased that DNTPH does detect the four different Aβ42 oligomers with conspicuous fluorescence (λ = 657 nm, λ = 639 nm, λ = 630 nm, and λ = 648 nm) but fails to distinguish them, indicating that additional improvements are required further for the probe to achieve it. The inhibition mechanisms of DNTPH on the four Aβ42 aggregation are however of amazing differences. For P and P, aggregation was inhibited by altering the secondary structural composition, i.e., by decreasing the β-sheet and toxic turn (residues 22-23) probabilities, respectively. For P, inhibition was achieved by segregating and keeping the two disordered monomeric species (P) away from the ordered secondary seed species (P) and consequently blocking further growth of the P seed. The inhibition mechanism for P is first probed and proposed so far, as far as we know, and the corresponding aggregation stage of P is the most important one among the four stages. The inhibition of P was triggered by distorting the fibril chains, disrupting the ordered fibril surface for the contact of monomers. In addition, the optimal inhibitory concentrations of DNTPH for P, P, and P were determined to be 1:3, while for P, it was 1:5. This outcome offers a novel perspective for designing drugs targeting Aβ42 oligomers at different aggregation stages.
β淀粉样蛋白（Aβ）42 聚集被认为与阿尔茨海默病（AD）的发病机制有关，但目前尚无有效的治疗方法。未来的临床试验应将抗淀粉样蛋白治疗策略应用于临床前阶段，并“越早越好”。因此，如何在不同的聚集阶段识别和抑制 Aβ42 寡聚体成为控制初级聚集和随后 AD 发展的关键。最近，人们发现了一种聚集诱导发射探针 DNTPH，能够在 710nm 波长下检测淀粉样蛋白，并在低剂量下对 Aβ纤维化表现出强烈的抑制作用。然而，不同早期聚集阶段 Aβ 寡聚体的检测和抑制机制仍不清楚。为此，我们构建了四种不同形态的 Aβ42 五聚体，其特征是单体聚集产物（P）、初级成核产物（P）、次级成核产物（P）和纤维状产物（P），以探索 DNTPH 在不同浓度下与不同产物结合的可区分能力和抑制机制。结果表明，DNTPH 确实可以检测到四种不同的 Aβ42 寡聚体，表现出明显的荧光（λ=657nm，λ=639nm，λ=630nm 和 λ=648nm），但无法区分它们，这表明需要进一步改进探针以实现这一目标。然而，DNTPH 对四种 Aβ42 聚集的抑制机制却有很大的不同。对于 P 和 P，通过改变二级结构组成来抑制聚集，即分别降低β-折叠和有毒转角（残基 22-23）的概率。对于 P，通过分离并使两个无序单体物种（P）远离有序二级种子物种（P）来实现抑制，从而阻止 P 种子进一步生长。据我们所知，目前首次探测并提出了 P 的抑制机制，而 P 的聚集阶段是四个阶段中最重要的阶段。P 的抑制是通过扭曲纤维链、破坏有序纤维表面以阻止单体接触来触发的。此外，确定了 DNTPH 对 P、P 和 P 的最佳抑制浓度分别为 1:3，而对于 P，最佳抑制浓度为 1:5。这一结果为设计针对不同聚集阶段 Aβ42 寡聚体的药物提供了新的视角。
Biochemistry. 2019-11-4
ACS Chem Neurosci. 2019-11-22
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