Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350112, Fujian Province, China; School of Pharmacy, Fujian Medical University, Fuzhou 350112, Fujian Province, China.
Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350112, Fujian Province, China; Department of Anesthesiology, Anesthesiology Research Institute, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China.
Life Sci. 2024 Nov 15;357:123085. doi: 10.1016/j.lfs.2024.123085. Epub 2024 Oct 1.
Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) aggregation and neuroinflammation, leading to progressive synaptic loss and cognitive decline. Recent evidence suggests that Galectin-3 (Gal-3) plays a critical role in Aβ pathogenesis. However, strategies to simultaneously target Gal-3 and Aβ are currently insufficient. This study evaluates the therapeutic efficacy of (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), in reducing Gal-3 and Aβ pathogenesis.
We applied exogenous oligomeric Aβ and used 5 × FAD mice to assess the impact of Aβ on Gal-3 deposition, microglial activation, and cognitive function. Thy1-EGFP mice were employed to observe dendritic spines. Comprehensive evaluations of D30's effects included behavioral studies, transcriptomic analysis, Western blotting, and immunofluorescent staining. The interaction between D30 and Gal-3 was examined using fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST).
D30 effectively reduced Aβ monomer production by inhibiting Amyloid Precursor Protein (APP) and presenilin 1 (PS1) expression, and decreased Aβ aggregation. Treatment with D30 improved cognitive functions, reversed dendritic spine loss, and increased PSD95 expression in 5 × FAD mice. Additionally, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. D30 binds to Gal-3 and disrupts the interaction between Gal-3 and TREM2, as confirmed by FRET and MST.
Our findings underscore the interaction between Gal-3 and Aβ in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aβ is crucial for preventing neuroinflammation and protecting synapses, D30 emerged as a novel compound with promising potential for AD treatment.
阿尔茨海默病（AD）的特征是β-淀粉样蛋白（Aβ）聚集和神经炎症，导致突触逐渐丧失和认知能力下降。最近的证据表明半乳糖凝集素-3（Gal-3）在 Aβ发病机制中起着关键作用。然而，目前同时针对 Gal-3 和 Aβ 的策略还不够。本研究评估了（E）-2-（3,4-二羟基苯乙烯基）-3-羟基-4H-吡喃-4-酮（D30）减少 Gal-3 和 Aβ发病机制的治疗效果。
我们应用外源性寡聚 Aβ并用 5×FAD 小鼠评估 Aβ对 Gal-3 沉积、小胶质细胞激活和认知功能的影响。使用 Thy1-EGFP 小鼠观察树突棘。D30 影响的综合评估包括行为研究、转录组分析、Western blotting 和免疫荧光染色。使用荧光共振能量转移（FRET）和微尺度热泳（MST）检测 D30 与 Gal-3 之间的相互作用。
D30 通过抑制淀粉样前体蛋白（APP）和早老素 1（PS1）的表达有效减少 Aβ单体的产生，并减少 Aβ 聚集。在 5×FAD 小鼠中，D30 治疗可改善认知功能、逆转树突棘丢失并增加 PSD95 表达。此外，D30 还显著降低了血浆和海马组织中的 Gal-3 水平。FRET 和 MST 证实，D30 与 Gal-3 结合并破坏 Gal-3 与 TREM2 之间的相互作用。
我们的研究结果强调了 5×FAD 小鼠模型中 Gal-3 与 Aβ 之间的相互作用及其在全身炎症中的作用。能够同时针对和调节 Gal-3 与 Aβ 对于预防神经炎症和保护突触至关重要，D30 作为一种具有治疗 AD 潜力的新型化合物脱颖而出。
