UCL Genetics Institute, UCL, London, UK.
Centre for Psychiatry, Queen Mary University of London, London, UK.
Ann Hum Genet. 2021 Jan;85(1):1-6. doi: 10.1111/ahg.12410. Epub 2020 Dec 1.
A variety of findings from in vitro experiments and animal models support the hypothesis that one contribution to pathogenesis in Alzheimer's disease (AD) is enhanced phosphorylation of tau protein, which may be triggered by amyloid β (Aβ) and mediated by impaired activity of the PI3K/Akt signaling pathway. A number of tyrosine phosphatases act to reduce PI3K/Akt activity, and inhibition of tyrosine phosphatases is protective against Aβ toxicity in cell cultures and whole animals. Results from analysis of exome sequenced late onset AD cases and controls similarly show that rare coding variants predicted to damage PI3K functioning increase AD risk, whereas those which are predicted to damage genes for tyrosine phosphatase genes are protective. Taken together, these results support the proposition that tyrosine phosphatase antagonists might be trialed as therapeutic agents to protect against the development of AD.
各种体外实验和动物模型的研究结果支持这样一种假设，即在阿尔茨海默病（AD）的发病机制中，tau 蛋白的过度磷酸化是一个重要因素，这种过度磷酸化可能是由淀粉样蛋白β（Aβ）触发的，并由 PI3K/Akt 信号通路活性受损所介导。许多酪氨酸磷酸酶的作用是降低 PI3K/Akt 的活性，而抑制酪氨酸磷酸酶对细胞培养物和整个动物中的 Aβ 毒性具有保护作用。对外显子组测序的迟发性 AD 病例和对照的分析结果也表明，预测会损害 PI3K 功能的罕见编码变异会增加 AD 的风险，而那些预测会损害酪氨酸磷酸酶基因的变异则具有保护作用。综上所述，这些结果支持这样一种观点，即酪氨酸磷酸酶拮抗剂可能被试用于治疗 AD，以防止其发生。
