Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

Abstract

Emerging experimental evidence suggests tau pathology spreads between neuroanatomically connected brain regions in a prion-like manner in Alzheimer's disease (AD). Tau seeding, the ability of prion-like tau to recruit and misfold na€ ıve tau to generate new seeds, is detected early in human AD brains before the development of major tau pathology. Many antitumour drugs have been reported to confer protection against neurodegeneration, supporting the repurposing of approved and experimental or investigational oncology drugs for AD therapy. In this study, we evaluated whether antitumour drugs that abrogate the generation of seed-competent aggregates of tau Repeat 3 (R3) domain peptides can prevent tau seeding and toxicity in Tau-RD P301S FRET Biosensor cells and Caenorhabditis elegans. We demonstrate that drugs that interact with the N-terminal VQI-VYK or the C-terminal region housing the Cys322 prevent R3 dimerisation, abolishing the generation of prion-like R3 seeds. Preformed R3 seeds (fibrils) capped with, or R3 seeds formed in the presence of VQIVYK-or Cys322-targeting drugs have a reduced potency to cause aggregation of na€ ıve tau in biosensor cells and protect worms from aggregate toxicity. These findings indicate that VQIVYK-or Cys322-targeting drugs may act as prophylactic agents against tau seeding.

Differential seeding by exogenous R2 and R3 fibrils influences autophagic degradation of intracellular tau aggregates in Tau K18 P301S cells

“…We found in our earlier study that intracellular seeding in cells induced with R3 fibrils corresponds to reduced cell growth [31]. In this study, we observed the decreased proliferation of R2 and R3-induced cells.…”

“…[30]. We previously reported a reduction in the growth of cells induced with R3 fibrils [31]. Therefore, we examined phospho-Histone H3 (Ser10) levels in the cell population sorted based on 0, 50 and 100% intracellular aggregate positivity (Ag+) after induction with R2 and R3 (Fig.…”

2-Aminothiazole-Flavonoid Hybrid Derivatives Binding to Tau Protein and Responsible for Antitumor Activity in Glioblastoma

“…Overall, it has been reported that many VQIVYK inhibitors can block the heparin-induced assembly of full-length Tau [60][61][62]. Recently, the Das' team reported by AFM analysis that 10 µM QCT abrogated R3 peptide fibrillation [63]. More interestingly, the authors demonstrated that QCT was able to prevent seeding of endogenous Tau aggregates by exogenous seeds.…”

Antineoplastics for treating Alzheimer's disease and dementia: Evidence from preclinical and observational studies

“…319 Similarly, we recently showed that drugs like paclitaxel, doxorubicin, resveratrol, and quercetin that interact with the amyloid motif and cysteine residue in tau repeat 3 block its nucleation-dependent aggregation, abolishing the formation of toxic, pathological prion-like aggregates of tau. 321 The concept of removal of a toxic burden of misfolded proteins is not new. Sequestering oligomers from human patients with tau-positive inclusions in brains is expected to abolish tau spreading, even after pathological tau deposition has begun.…”