1. A tau dephosphorylation-targeting chimeraselectively recruits protein phosphatase-1 to ameliorate Alzheimer's disease and tauopathies.
- Author
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Xiao, Yue, Wei, Linyu, Su, Jingfen, Lei, Huiyang, Sun, Fei, Li, Mengzhu, Li, Shihong, Wang, Xiaochuan, Zheng, Jie, and Wang, Jian-Zhi
- Subjects
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ALZHEIMER'S disease , *TAUOPATHIES , *PHOSPHOPROTEIN phosphatases , *PEPTIDES , *NEUROPLASTICITY - Abstract
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. [Display omitted] • A DEPTAC peptide, D20, recruits PP1 to promote tau dephosphorylation • D20 can effectively penetrate the blood-brain barrier with low cytotoxicity • D20 ameliorates tau pathology and enhances synaptic plasticity • D20 improves the cognitive functions in AD models Xiao et al. apply the concept of dephosphorylation targeting chimera (DEPTAC) and develop D20, a proximity-inducing peptide that facilitates the interaction between tau and protein phosphatase 1 (PP1) to reduce tau hyperphosphorylation. D20 enhances synaptic function and cognitive functions in AD mice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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