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

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.

Exploitation of Marine Molecules to Manage Alzheimer’s Disease

“…In addition, studies suggest that the intracellular accumulation of tau is a key factor in the memory deficits and the neurodegeneration in AD; therefore, the development of drugs aimed at tau clearance has gained attention in recent years [ 29 ]. Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) to degrade specific proteins from within cells represents a promising novel therapeutic strategy for AD and the related tauopathies [ 30 ]. As PROTACs could potentially be generated for any protein, they may be used to target tau, a natively unfolded undruggable protein.…”

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

“…Another small molecule, C004019, designed to bind both monomeric Tau and Vhl ubiquitin ligase efficiently targeted it for degradation by the proteasome in cellular and mouse models. 605 C004019 was efficient at improving synaptic and cognitive deficits in hTau and 3XTg-AD mice. The reduction in the high molecular weight Tau observed was attributed to the shift in the equilibrium between soluble monomeric and oligomeric or aggregated Tau species.…”

Tau in Health and Neurodegenerative Diseases

“…E3 ubiquitin ligase stimulates polyubiquitination of the targets and facilitates its following recognition and degradation by the 26S proteasome [149]. PROTACs targeting tau remarkably decreased tau levels and improved synaptic and cognitive functions in wildtype and AD mice [150].…”