Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 171 64 Stockholm, Sweden.
Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, 171 64 Stockholm, Sweden.
Int J Mol Sci. 2021 Sep 20;22(18):10139. doi: 10.3390/ijms221810139.
The activation of the brain renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cognition. While the brain RAS has been studied before in the context of hypertension, little is known about its role and regulation in relation to neuronal function and its modulation. Adequate blood flow to the brain as well as proper clearing of metabolic byproducts become crucial in the presence of neurodegenerative disorders such as Alzheimer's disease (AD). RAS inhibition (RASi) drugs that can cross into the central nervous system have yielded unclear results in improving cognition in AD patients. Consequently, only one RASi therapy is under consideration in clinical trials to modify AD. Moreover, the role of non-genetic factors such as hypercholesterolemia in the pathophysiology of AD remains largely uncharacterized, even when evidence exists that it can lead to alteration of the RAS and cognition in animal models. Here we revise the evidence for the function of the brain RAS in cognition and AD pathogenesis and summarize the evidence that links it to hypercholesterolemia and other risk factors. We review existent medications for RASi therapy and show research on novel drugs, including small molecules and nanodelivery strategies that can target the brain RAS with potential high specificity. We hope that further research into the brain RAS function and modulation will lead to innovative therapies that can finally improve AD neurodegeneration.
脑肾素-血管紧张素系统 (RAS) 的激活在认知的病理生理学中起着关键作用。虽然脑 RAS 在高血压的背景下已经得到了研究，但关于其在神经元功能及其调节方面的作用和调节知之甚少。在神经退行性疾病（如阿尔茨海默病（AD））中，适当的大脑血流和代谢产物的适当清除变得至关重要。能够进入中枢神经系统的 RAS 抑制 (RASi) 药物在改善 AD 患者认知方面的结果并不明确。因此，只有一种 RASi 疗法正在临床试验中考虑用于改变 AD。此外，即使有证据表明它可以导致 RAS 和认知在动物模型中的改变，但诸如高胆固醇血症等非遗传因素在 AD 发病机制中的作用在很大程度上仍未得到阐明。在这里，我们回顾了脑 RAS 在认知和 AD 发病机制中的功能的证据，并总结了将其与高胆固醇血症和其他危险因素联系起来的证据。我们审查了用于 RASi 治疗的现有药物，并展示了针对脑 RAS 的新型药物的研究，包括具有潜在高特异性的小分子和纳米递药策略。我们希望对脑 RAS 功能和调节的进一步研究将导致创新的治疗方法，最终改善 AD 神经退行性变。
