1. Academic Validation
  2. A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models

A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models

  • Theranostics. 2021 Mar 11;11(11):5279-5295. doi: 10.7150/thno.55680.
Weijin Wang 1 Qiuzhi Zhou 1 Tao Jiang 1 Shihong Li 1 Jinwang Ye 1 Jie Zheng 1 Xin Wang 1 Yanchao Liu 1 Minmin Deng 1 Dan Ke 1 Qun Wang 1 Yipeng Wang 2 Jian-Zhi Wang 1 3
Affiliations

Affiliations

  • 1 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Neurosmart Therapeutics Co., Ltd., Room 5013, Unit 1, Buiilding 7, Basheng road 160, Shanghai 200131, China.
  • 3 Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226000, China.
Abstract

Intracellular accumulation of tau is a hallmark pathology in Alzheimer disease (AD) and the related tauopathies, thus targeting tau could be promising for drug development. Proteolysis Targeting Chimera (PROTAC) is a novel drug discovery strategy for selective protein degradation from within cells. Methods: A novel small-molecule PROTAC, named as C004019 with a molecular mass of 1,035.29 dalton, was designed to simultaneously recruite tau and E3-ligase (Vhl) and thus to selectively enhance ubiquitination and proteolysis of tau proteins. Western blotting, immunofluoresence and immunohistochemical staining were employed to verify the effects of C004019 in cell models (HEK293 and SH-SY5Y) and mouse models (hTau-transgenic and 3xTg-AD), respectively. The cognitive capacity of the mice was assessed by a suite of behavior experiments. Electrophysiology and Golgi staining were used to evaluate the synaptic plasticity. Results: C004019 induced a robust tau clearance via promoting its ubiquitination-proteasome-dependent proteolysis in HEK293 cells with stable or transient overexpression of human tau (hTau), and in SH-SY5Y that constitutively overexpress hTau. Furthermore, intracerebral ventricular infusion of C004019 induced a robust tau clearance in vivo. Most importantly, both single-dose and multiple-doses (once per 6 days for a total 5 times) subcutaneous administration of C004019 remarkably decreased tau levels in the brains of wild-type, hTau-transgenic and 3xTg-AD mice with improvement of synaptic and cognitive functions. Conclusions: The PROTAC (C004019) created in the current study can selectively and efficiently promote tau clearance both in vitro and in vivo, which provides a promising drug candidate for AD and the related tauopathies.

Keywords

Alzheimer's disease; C004019; proteolysis targeting chimeras; tau; tauopathies.

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