4.7 Article

A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies

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SPRINGERNATURE
DOI: 10.1038/s41392-021-00669-2

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资金

  1. National Key R&D Program of China [2016YFC1305800]
  2. Special project of technological innovation of Hubei Province [2018ACA142]
  3. Natural Science Foundation of China [31730035, 81721005, 91949205, 81901107]
  4. China Postdoctoral Science Foundation [2018M632872]
  5. Guangdong Provincial Key ST Program [2018B030336001]
  6. Science and Technology Program of Guizhou Province [423]

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The novel DEPTAC designed and synthesized in this study effectively dephosphorylates tau at AD-associated sites and prevents its accumulation. DEPTAC improves microtubule assembly, synaptic plasticity, and hippocampus-dependent learning and memory, providing a new strategy for the targeted therapy of AD and related tauopathies.
Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer's disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to B alpha -subunit-containing protein phosphatase 2A (PP2A-B alpha), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.

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