1. A tau dephosphorylation-targeting chimeraselectively recruits protein phosphatase-1 to ameliorate Alzheimer's disease and tauopathies.
- Author
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Xiao Y, Wei L, Su J, Lei H, Sun F, Li M, Li S, Wang X, Zheng J, and Wang JZ
- Subjects
- Animals, Mice, Phosphorylation drug effects, Humans, Neurons drug effects, Neurons metabolism, Neurons pathology, Mice, Transgenic, Cells, Cultured, Disease Models, Animal, Mice, Inbred C57BL, Peptides chemistry, Peptides pharmacology, Hippocampus metabolism, Hippocampus drug effects, tau Proteins metabolism, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Alzheimer Disease pathology, Tauopathies drug therapy, Tauopathies metabolism, Tauopathies pathology, Protein Phosphatase 1 metabolism, Protein Phosphatase 1 antagonists & inhibitors
- 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., Competing Interests: Declaration of interests We, the authors, have applied for a patent related to this work, and the patent application is pending., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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