Alalwany Roaa H, Hawtrey Tom, Morgan Kevin, Morris Jonathan C, Donaldson Lucy F, Bates David O
Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
Front Mol Neurosci. 2023 Jun 27;16:1181626. doi: 10.3389/fnmol.2023.1181626. eCollection 2023.
Alzheimer's disease (AD) is the most common cause of dementia, the chronic and progressive deterioration of memory and cognitive abilities. AD can be pathologically characterised by neuritic plaques and neurofibrillary tangles, formed by the aberrant aggregation of β-amyloid and tau proteins, respectively. We tested the hypothesis that VEGF isoforms VEGF-Aa and VEGF-Ab, produced by differential splice site selection in exon 8, could differentially protect neurons from neurotoxicities induced by β-amyloid and tau proteins, and that controlling expression of splicing factor kinase activity could have protective effects on AD-related neurotoxicity . Using oxidative stress, β-amyloid, and tau hyperphosphorylation models, we investigated the effect of VEGF-A splicing isoforms, previously established to be neurotrophic agents, as well as small molecule kinase inhibitors, which selectively inhibit SRPK1, the major regulator of VEGF splicing. While both VEGF-Aa and VEGF-Ab isoforms were protective against AD-related neurotoxicity, measured by increased metabolic activity and neurite outgrowth, VEGF-Aa was able to enhance neurite outgrowth but VEGF-Ab did not. In contrast, VEGF-Ab was more effective than VEGF-Aa in preventing neurite "dieback" in a tau hyperphosphorylation model. SRPK1 inhibition was found to significantly protect against neurite "dieback" through shifting AS of towards the VEGF-Ab isoform. These results indicate that controlling the activities of the two different isoforms could have therapeutic potential in Alzheimer's disease, but their effect may depend on the predominant mechanism of the neurotoxicity-tau or β-amyloid.
阿尔茨海默病（AD）是痴呆最常见的病因，表现为记忆和认知能力的慢性进行性衰退。AD的病理特征是分别由β-淀粉样蛋白和tau蛋白异常聚集形成的神经炎性斑块和神经原纤维缠结。我们检验了以下假设：通过外显子8中不同剪接位点选择产生的VEGF亚型VEGF-Aa和VEGF-Ab，可能对β-淀粉样蛋白和tau蛋白诱导的神经毒性具有不同的神经保护作用，并且控制剪接因子激酶活性可能对AD相关神经毒性具有保护作用。利用氧化应激、β-淀粉样蛋白和tau过度磷酸化模型，我们研究了先前确定为神经营养因子的VEGF-A剪接亚型以及选择性抑制VEGF剪接主要调节因子SRPK1的小分子激酶抑制剂的作用。通过增加代谢活性和神经突生长来衡量，VEGF-Aa和VEGF-Ab亚型均对AD相关神经毒性具有保护作用，但VEGF-Aa能够促进神经突生长，而VEGF-Ab则不能。相反，在tau过度磷酸化模型中，VEGF-Ab在预防神经突“回缩”方面比VEGF-Aa更有效。发现抑制SRPK1可通过使剪接向VEGF-Ab亚型转变而显著预防神经突“回缩”。这些结果表明，控制这两种不同亚型的活性可能对阿尔茨海默病具有治疗潜力，但其效果可能取决于神经毒性的主要机制——tau或β-淀粉样蛋白。
