A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies

Abstract

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 Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), 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.

Multifaceted targeted protein degradation systems for different cellular compartments

“…14,15 DEPTAC was developed within the last year to reduce pathological levels of hyperphosphorylated tau protein. 13 Compared to less selective strategies relying either on kinase inhibitors or on phosphatase activators, this strategy brings protein phosphatase 2A-Bα (PP2A-Bα) in proximity to tau, in a conceptual design that resembles PROTACs. In essence, the DEPTAC molecule consists of a tau binding peptide fused by a linker to a PP2A-Bα-recruiting peptide and a C-terminal cell-penetrating peptide.…”

“…13 In an elegant series of proofof-concept experiments, the authors demonstrated that the DEPTAC bound to both tau and to PP2A-Bα in vitro, while a control chimera harbouring mutations in both of these domains did not. 13…”

“…A variation of PROTAC, called DEPTAC, was recently developed to selectively remove phospho‐proteins 13 . Traditional PROTACs directed against total tau protein associated with frontotemporal dementia (FTD) and Alzheimer's disease pathology have been generated previously 14,15 .…”

Microglia, TREM2, and Therapeutic Methods of Alzheimer’s Disease

“…Tau hyperphosphorylation causes abnormal aggregation and neurodegeneration in AD brains [141], and protein phosphatase 2A (PP2A) has the most robust dephosphorylation activity to tau protein in vitro and in vivo [142]. A novel DEPho-sphorylation Targeting Chimaera (DEPTAC) was designed to enhance the combination of tau and PP2A-Bα, which shows high efficiency in preventing tau accumulation in vitro and in vivo [143]. Further studies showed that DEPAC significantly improved the microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice [143].…”

“…A novel DEPho-sphorylation Targeting Chimaera (DEPTAC) was designed to enhance the combination of tau and PP2A-Bα, which shows high efficiency in preventing tau accumulation in vitro and in vivo [143]. Further studies showed that DEPAC significantly improved the microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice [143].…”