Department for Neuroscience, Croatian Institute for Brain Research, University of Zagreb Medical School, Zagreb, Croatia.
Nash Family Department of Neuroscience, Friedman Brain Institute, and Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Prog Brain Res. 2021;261:379-421. doi: 10.1016/bs.pbr.2020.07.016. Epub 2021 Jan 20.
The pathogenesis of Alzheimer's disease (AD) is not fully understood. Here we summarize current knowledge on the involvement of the serotonergic, noradrenergic, dopaminergic, cholinergic, and opioid systems in AD, emphasizing the importance of interactions between the serotonergic and the other subcortical modulatory systems during the progression of AD. In physiological conditions, all neurotransmitter systems function in concert and are interdependent at both the neuroanatomical and molecular levels. Through their early involvement in AD, cognitive and behavioral abilities that rely on their interactions also become disrupted. Considering that serotonin (5HT) regulates the release of noradrenaline (NA), dopamine (DA) and acetylcholine (ACh), any alteration in 5HT levels leads to disturbance of NA, DA, and ACh homeostasis in the brain. One of the earliest pathological changes during the prodromal phase of AD is a decrease of serotonergic transmission throughout the brain, with serotonergic receptors being also affected. Additionally, serotonergic and noradrenergic as well as serotonergic and dopaminergic nuclei are reciprocally interconnected. As the serotonergic dorsal raphe nucleus (DRN) is affected by pathological changes early in AD, and the noradrenergic locus coeruleus (LC) and dopaminergic ventral tegmental area (VTA) exhibit AD-related pathological changes, their connectivity also becomes altered in AD. Such disrupted interactions among neurotransmitter systems in AD can be used in the development of multi-target drugs. Some of the potential AD therapeutics (such as ASS234, RS67333, tropisetron) target multiple neurotransmitter systems to achieve the best possible improvement of cognitive and behavioral deficits observed in AD. Here, we review how serotonergic system interacts with other subcortical modulatory systems (noradrenergic, dopaminergic, cholinergic, and opioid systems) during AD.
阿尔茨海默病（AD）的发病机制尚未完全阐明。在这里，我们总结了目前关于 5-羟色胺能、去甲肾上腺素能、多巴胺能、胆碱能和阿片能系统在 AD 中的作用的知识，强调了 AD 进展过程中 5-羟色胺能系统与其他皮质下调节系统相互作用的重要性。在生理条件下，所有神经递质系统都协同工作，并在神经解剖和分子水平上相互依赖。通过它们在 AD 中的早期参与，依赖于它们相互作用的认知和行为能力也会受到干扰。考虑到 5-羟色胺（5HT）调节去甲肾上腺素（NA）、多巴胺（DA）和乙酰胆碱（ACh）的释放，5HT 水平的任何改变都会导致大脑中 NA、DA 和 ACh 稳态的紊乱。AD 前驱期最早的病理变化之一是整个大脑中 5-羟色胺传递的减少，5-羟色胺受体也受到影响。此外，5-羟色胺能和去甲肾上腺素能以及 5-羟色胺能和多巴胺能核是相互连接的。由于 AD 早期 5-羟色胺能背侧中缝核（DRN）受到病理变化的影响，而去甲肾上腺素能蓝斑核（LC）和多巴胺能腹侧被盖区（VTA）则表现出与 AD 相关的病理变化，因此它们的连接在 AD 中也发生了改变。AD 中神经递质系统之间这种中断的相互作用可用于开发多靶点药物。一些潜在的 AD 治疗药物（如 ASS234、RS67333、tropisetron）针对多个神经递质系统，以尽可能改善 AD 中观察到的认知和行为缺陷。在这里，我们综述了 5-羟色胺能系统在 AD 期间如何与其他皮质下调节系统（去甲肾上腺素能、多巴胺能、胆碱能和阿片能系统）相互作用。
