Zhu Bangfu, Parsons Tom, Stensen Wenche, Mjøen Svendsen John S, Fugelli Anders, Hodge James J L
School of Physiology, Pharmacology and Neuroscience, Faculty of Life Science, University of Bristol, Bristol, United Kingdom.
Department of Chemistry, The Arctic University of Norway, Tromsø, Norway.
Front Pharmacol. 2022 Jul 19;13:881385. doi: 10.3389/fphar.2022.881385. eCollection 2022.
Alzheimer's disease (AD) is the most common neurodegenerative disease which is becoming increasingly prevalent due to ageing populations resulting in huge social, economic, and health costs to the community. Despite the pathological processing of genes such as () into Amyloid-β and () gene, into hyperphosphorylated Tau tangles being known for decades, there remains no treatments to halt disease progression. One population with increased risk of AD are people with Down syndrome (DS), who have a 90% lifetime incidence of AD, due to trisomy of human chromosome 21 (HSA21) resulting in three copies of and other AD-associated genes, such as (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) overexpression. This suggests that blocking DYRK1A might have therapeutic potential. However, it is still not clear to what extent DYRK1A overexpression by itself leads to AD-like phenotypes and how these compare to Tau and Amyloid-β mediated pathology. Likewise, it is still not known how effective a DYRK1A antagonist may be at preventing or improving any Tau, Amyloid-β and DYRK1a mediated phenotype. To address these outstanding questions, we characterised models with targeted overexpression of human , human or the fly orthologue of , called (). We found targeted overexpression of these AD-associated genes caused degeneration of photoreceptor neurons, shortened lifespan, as well as causing loss of locomotor performance, sleep, and memory. Treatment with the experimental DYRK1A inhibitor PST-001 decreased pathological phosphorylation of human Tau [at serine (S) 262]. PST-001 reduced degeneration caused by human Tau, Amyloid-β or mnb lengthening lifespan as well as improving locomotion, sleep and memory loss caused by expression of these AD and DS genes. This demonstrated PST-001 effectiveness as a potential new therapeutic targeting AD and DS pathology.
阿尔茨海默病（AD）是最常见的神经退行性疾病，由于人口老龄化，其发病率日益上升，给社会、经济和健康带来了巨大成本。尽管诸如（）基因加工成β淀粉样蛋白以及（）基因加工成过度磷酸化的Tau缠结这一病理过程已为人所知数十年，但仍没有能够阻止疾病进展的治疗方法。患AD风险增加的人群之一是唐氏综合征（DS）患者，由于人类21号染色体（HSA21）三体性导致（）和其他AD相关基因有三个拷贝，他们一生中患AD的几率为90%，比如（双特异性酪氨酸磷酸化调节激酶1A）的过表达。这表明阻断DYRK1A可能具有治疗潜力。然而，目前尚不清楚DYRK1A过表达本身在多大程度上会导致类AD表型，以及这些表型与Tau和β淀粉样蛋白介导的病理变化相比情况如何。同样，目前也不清楚DYRK1A拮抗剂在预防或改善任何Tau、β淀粉样蛋白和DYRK1A介导的表型方面的效果如何。为了解决这些悬而未决的问题，我们对靶向过表达人类（）、人类（）或其果蝇同源物（称为（））的模型进行了表征。我们发现这些AD相关基因的靶向过表达导致光感受器神经元退化、寿命缩短，以及导致运动能力、睡眠和记忆丧失。用实验性DYRK1A抑制剂PST - 001进行治疗可降低人类Tau [丝氨酸（S）262位点]的病理性磷酸化。PST - 001减少了由人类Tau、β淀粉样蛋白或mnb引起的退化，延长了寿命，同时改善了由这些AD和DS基因表达所导致的运动、睡眠和记忆丧失。这证明了PST - 001作为一种针对AD和DS病理的潜在新疗法的有效性。
