Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0AH, UK.
Department of Clinical Neurosciences, UK Dementia Research Institute, University of Cambridge, Cambridge CB2 0AH, UK.
Int J Mol Sci. 2022 Feb 11;23(4):2021. doi: 10.3390/ijms23042021.
Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world's population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed-particularly any that can slow down the disease's progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents-in particular the licensed antidepressant trazodone-and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia.
痴呆症是一个全球性的医学和社会挑战；它给个人、社会和经济带来了毁灭性的影响，而且随着世界人口老龄化，这些影响将会迅速加剧。尽管如此，目前还没有针对痴呆症的治疗方法可以改变疾病进程；现有的治疗方法只能适度改善症状，但无法改变疾病的结局。因此，急需新的治疗方法——尤其是那些可以减缓疾病进展的治疗方法。许多导致痴呆的神经退行性疾病的特征是脑细胞中异常蛋白质产生和错误折叠的共同病理反应，这为广泛应用针对这些共同过程的治疗方法提供了可能性。未折叠蛋白反应（UPR）就是这样一种机制。UPR 是一种对异常蛋白质折叠的高度保守的细胞应激反应，在神经退行性疾病中广泛失调。在这篇综述中，我们描述了 UPR 的基本机制，以及其在痴呆症中的过度激活和致病性的证据，以及在这些疾病的小鼠模型中对其进行治疗性干预的显著神经保护作用。我们讨论了已确定的潜在 UPR 修饰治疗药物——特别是已获许可的抗抑郁药曲唑酮——并回顾了其在人类中的使用的流行病学和试验数据。最后，我们探讨了在痴呆症患者中使用曲唑酮或类似的 UPR 调节化合物进行疾病修饰的潜在益处的未来研究方向。
