论文标题

血清素能药物作用在阿尔茨海默氏病中的多尺度计算建模的机会

Opportunities for multiscale computational modelling of serotonergic drug effects in Alzheimer's disease

论文作者

Joshi, Alok, Wang, Da-Hui, Watterson, Steven, McClean, Paula L., Behera, Chandan K., Sharp, Trevor, Wong-Lin, KongFatt

论文摘要

阿尔茨海默氏病(AD)是一种特异性的神经退行性疾病,会损害认知功能并影响个人的生活质量。从病理上讲,AD的特征是β-淀粉样蛋白($β$)和热磷酸化的tau蛋白的异常积累。尽管在过去几十年中的研究进展,但目前仍无法治愈广告。尽管可以使用药物来控制某些行为症状并减缓疾病的进展,但大多数处方药都是基于胆碱酯酶抑制剂。在过去的十年中,人们对新型药物的关注越来越大,瞄准了替代性神经递质途径,尤其是那些针对血清素能(5-HT)系统的途径。在这篇综述中,我们专注于针对这些受体的5-HT受体(5-HTR)介导的信号传导和药物。这些途径调节关键蛋白和激酶,例如GSK-3,与AD中的$β$和tau的水平异常相关。然后,我们回顾了与5-HT信号通路相关的计算研究,并有可能深入了解AD病理。特别是,我们建议多尺度和多级建模方法可能会提供有关AD机制的新见解,并旨在发现基于5-HTR的新型治疗靶标。

Alzheimer's disease (AD) is an age-specific neurodegenerative disease that compromises cognitive functioning and impacts the quality of life of an individual. Pathologically, AD is characterised by abnormal accumulation of beta-amyloid (A$β$) and hyperphosphorylated tau protein. Despite research advances over the last few decades, there is currently still no cure for AD. Although, medications are available to control some behavioural symptoms and slow the disease's progression, most prescribed medications are based on cholinesterase inhibitors. Over the last decade, there has been increased attention towards novel drugs, targeting alternative neurotransmitter pathways, particularly those targeting serotonergic (5-HT) system. In this review, we focused on 5-HT receptor (5-HTR) mediated signalling and drugs that target these receptors. These pathways regulate key proteins and kinases such as GSK-3 that are associated with abnormal levels of A$β$ and tau in AD. We then review computational studies related to 5-HT signalling pathways with the potential for providing deeper understanding of AD pathologies. In particular, we suggest that multiscale and multilevel modelling approaches could potentially provide new insights into AD mechanisms, and towards discovering novel 5-HTR based therapeutic targets.

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