Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
Neuropharmacology. 2018 Mar 15;131:351-363. doi: 10.1016/j.neuropharm.2018.01.003. Epub 2018 Jan 5.
Alzheimer's disease (AD) is a progressive neurodegenerative dysfunction characterized by memory impairment and brings a heavy burden to old people both in developing and developed countries. Amyloid hypothesis reveals that aggregation and deposition of amyloid plaques are the cause of AD neurodegeneration. SLOH, a carbazole-based fluorophore, is reported to inhibit amyloid beta (Aβ) aggregation in vitro. In the current study, we intended to evaluate the protective effect of SLOH in a triple transgenic AD mouse model (3xTg-AD). 3xTg-AD (10-month-old) were treated with SLOH (0.5, 1 and 2 mg kg) for one month via intraperitoneal injection. After treatment, cognitive function was assessed by Morris Water Maze (MWM) and Y-maze tasks. In addition, biochemical estimations were used to examine the degree of Aβ deposition, tau hyperphosphorylation and neuroinflammation in the brains of 3xTg-AD mice. An in vitro study was conducted on human neuroblastoma (SH-SY5Y) cells to determine the activity of SLOH on tau and GSK-3β using western blot and immunofluorescence staining. One month treatment with SLOH significantly ameliorated memory impairments in 3xTg-AD mice in MWM and Y-maze tests. Moreover, SLOH treatment mitigated the level of amyloid plaques, tau hyperphosphorylation and neuroinflammation in the mouse brain. SLOH also reduced tau hyperphosphorylation and down-regulated GSK-3β activity in Aβ induced neurotoxic SH-SY5Y cells. The promising results in mitigating amyloid plaques, tau hyperphosphorylation, neuroinflammation and ameliorating cognitive deficits following one-month treatment suggest that SLOH could be a potential multi-target molecule for the AD treatment.
阿尔茨海默病（AD）是一种进行性神经退行性功能障碍，其特征是记忆障碍，给发展中国家和发达国家的老年人带来了沉重的负担。淀粉样蛋白假说表明，淀粉样斑块的聚集和沉积是 AD 神经退行性变的原因。SLOH 是一种咔唑基荧光团，据报道可抑制体外淀粉样β（Aβ）聚集。在本研究中，我们旨在评估 SLOH 在三转基因 AD 小鼠模型（3xTg-AD）中的保护作用。3xTg-AD（10 月龄）通过腹腔注射用 SLOH（0.5、1 和 2 mg/kg）治疗一个月。治疗后，通过 Morris 水迷宫（MWM）和 Y 迷宫任务评估认知功能。此外，还进行了生化评估，以检查 3xTg-AD 小鼠大脑中 Aβ沉积、tau 过度磷酸化和神经炎症的程度。在体外研究中，用人神经母细胞瘤（SH-SY5Y）细胞通过 Western blot 和免疫荧光染色来确定 SLOH 对 tau 和 GSK-3β 的活性。SLOH 治疗一个月可显著改善 3xTg-AD 小鼠在 MWM 和 Y 迷宫测试中的记忆障碍。此外，SLOH 治疗减轻了小鼠大脑中的淀粉样斑块、tau 过度磷酸化和神经炎症水平。SLOH 还降低了 Aβ 诱导的神经毒性 SH-SY5Y 细胞中的 tau 过度磷酸化并下调了 GSK-3β 活性。一个月的治疗减轻了淀粉样斑块、tau 过度磷酸化、神经炎症和改善认知障碍的有希望的结果表明，SLOH 可能是 AD 治疗的一种有潜力的多靶分子。
