Aix Marseille Univ, CNRS, NICN, Marseille, France.
IGF, CNRS, INSERM, Univ. Montpellier, F-34094 Montpellier, France.
Neuropharmacology. 2017 Nov;126:128-141. doi: 10.1016/j.neuropharm.2017.08.031. Epub 2017 Aug 26.
Alzheimer's disease (AD) is the main cause of dementia and a major health issue worldwide. The complexity of the pathology continues to challenge its comprehension and the implementation of effective treatments. In the last decade, a number of possible targets of intervention have been pointed out, among which the stimulation of 5-HT receptors (5-HTRs) seems very promising. 5-HTR agonists exert pro-cognitive effects, inhibit amyloid-β peptide (Aβ) production and therefore directly and positively impact AD progression. In the present work, we investigated the effects of RS 67333, a partial 5-HTR agonist, after chronic administration in the 5xFAD mouse model of AD. 5xFAD male mice and their wild type (WT) male littermates received either RS 67333 or vehicle solution i.p., twice a week, for 2 or 4 months. Cognitive performance was evaluated in a hippocampal-dependent behavioral task, the olfactory tubing maze (OTM). Mice were then sacrificed to evaluate the metabolism of the amyloid precursor protein (APP), amyloidosis and neuroinflammatory processes. No beneficial effects of RS 67333 were observed in 5xFAD mice after 2 months of treatment, while 5xFAD mice treated for 4 months showed better cognitive abilities compared to vehicle-treated 5xFAD mice. The beneficial effects of RS 67333 on learning and memory correlated with the decrease in both amyloid plaque load and neuroinflammation, more specifically in the entorhinal cortex. The most significant improvements in learning and memory and reduction of pathology stigmata were observed after the 4-month administration of RS 67333, demonstrating that treatment duration is important to alleviate amyloidosis and glial reactivity, particularly in the entorhinal cortex. These results confirm the 5-HTR as a promising target for AD pathogenesis and highlight the need for further investigations to characterize fully the underlying mechanisms of action.
阿尔茨海默病（AD）是痴呆症的主要病因，也是全球范围内的一个主要健康问题。该疾病的病理复杂性仍然是对其理解和实施有效治疗的挑战。在过去的十年中，已经指出了许多可能的干预靶点，其中 5-羟色胺受体（5-HTRs）的刺激似乎非常有前途。5-HTR 激动剂具有促认知作用，可抑制淀粉样β肽（Aβ）的产生，因此直接且积极地影响 AD 的进展。在本工作中，我们研究了 RS 67333（一种部分 5-HTR 激动剂）在 AD 的 5xFAD 小鼠模型中的慢性给药后的作用。5xFAD 雄性小鼠及其野生型（WT）雄性同窝仔鼠接受 RS 67333 或载体溶液腹腔内注射，每周两次，共 2 或 4 个月。在海马依赖性行为任务，嗅觉管迷宫（OTM）中评估认知表现。然后处死小鼠以评估淀粉样前体蛋白（APP）的代谢、淀粉样变性和神经炎症过程。在 2 个月的治疗后，5xFAD 小鼠未观察到 RS 67333 的有益作用，而治疗 4 个月的 5xFAD 小鼠与载体处理的 5xFAD 小鼠相比表现出更好的认知能力。RS 67333 对学习和记忆的有益作用与淀粉样斑块负荷和神经炎症的减少相关，特别是在海马旁回。在 RS 67333 给药 4 个月后，观察到学习和记忆的改善和病理学特征的减少最为显著，表明治疗持续时间对于减轻淀粉样变性和神经胶质反应，特别是在海马旁回是重要的。这些结果证实 5-HTR 是 AD 发病机制的有前途的靶点，并强调需要进一步研究以充分表征潜在的作用机制。
