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.
Highlights
Intraneuronal accumulation of the neurofibrillary tangles formed primarily by hyperphosphorylated tau is a hallmark of a collection of neurodegenerative disease named tauopathies, including Alzheimer’ disease (AD),[1,2] the most common form of dementia in the elderly
DEPTAC binds to tau and phosphatase 2A (PP2A) with high neuronal penetrability The DEPTAC (~4.4 kDa, C185H314N72O56) consists 38 amino acid residues from N-terminals to C-terminals and has four functional motifs (Fig. 1a): (1) YQQYQDATADEQG, originates from the porcine β-tubulin 422–434 for recognizing and binding tau proteins.[5,6] (2) GSGS, a linker for increasing the flexibility of the peptide.[15] (3) KKVAVVRTPPKSP, for recruiting PP2A-Bα,[16] and (4) RRRRRRRR, for
To further test the triadic interaction of DEPTAC with tau and PP2A-Bα, we developed a rabbit polyclonal antibody of DEPTAC using a fragment of DEQGGSGSKKVA (Supplementary Fig. S2)
Summary
Intraneuronal accumulation of the neurofibrillary tangles formed primarily by hyperphosphorylated tau is a hallmark of a collection of neurodegenerative disease named tauopathies, including Alzheimer’ disease (AD),[1,2] the most common form of dementia in the elderly. Multiple efforts are being made to reduce the tau accumulation in AD, by using such as tau antisense oligonucleotides,[3] antibodies,[4] PROteolysis TArgeting Chimeras (PROTACs),[5,6] and the structure-based tau aggregation inhibitors.[7,8] It is well known that tau hyperphosphorylation initiates the abnormal tau aggregation and induces neurodegeneration in the brains of AD and the related tauopathies,[9] there is currently no strategy for targeting tau phosphorylation at the post-translational level. An alternative strategy to inhibit tau hyperphosphorylation is to strengthen tau phosphatases. The heterotrimeric PP2A holoenzyme is consisted of a scaffold subunit A, a regulatory subunit B (recognizing and targeting substrates) and a catalytic subunit C
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