脱磷
疾病
τ蛋白
Tau病理学
蛋白磷酸酶2
磷酸酶
阿尔茨海默病
医学
老年学
神经科学
生物
磷酸化
内科学
生物化学
作者
Yue Xiao,Linyu Wei,Jingfen Su,Huiyang Lei,Fei Sun,Mengzhu Li,Shihong Li,Xiaochuan Wang,Jie Zheng,Jian‐Zhi Wang
标识
DOI:10.1016/j.chembiol.2024.09.003
摘要
Abnormal accumulation of hyperphosphorylated tau (pTau) is a major cause of neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Therefore, reducing pTau holds therapeutic promise for these diseases. Here, we developed a chimeric peptide, named D20, for selective facilitation of tau dephosphorylation by recruiting protein phosphatase 1 (PP1) to tau. PP1 is one of the active phosphatases that dephosphorylates tau. In both cultured primary hippocampal neurons and mouse models for AD or related tauopathies, we demonstrated that single-dose D20 treatment significantly reduced pTau by dephosphorylation at multiple AD-related sites and total tau (tTau) levels were also decreased. Multiple-dose administration of D20 through tail vein injection in 3xTg AD mice effectively ameliorated tau-associated pathologies with improved cognitive functions. Importantly, at therapeutic doses, D20 did not cause detectable toxicity in cultured neurons, neural cells, or peripheral organs in mice. These results suggest that D20 is a promising drug candidate for AD and related tauopathies.
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