Specific Knockdown of Endogenous Tau Protein by Peptide-Directed Ubiquitin-Proteasome Degradation.

Tau, an important pathological protein of Alzheimer's disease (AD), can mediate the toxicity of amyloid β (Aβ). Thus, reduction of Tau with chemical molecules may offer a novel strategy for treating AD. Here, we designed and synthesized a series of multifunctional molecules that contained Tau-recognition moieties and E3 ligase-binding moieties to enhance Tau degradation. Among these molecules, TH006 had the highest activity of inducing Tau degradation by increasing its poly-ubiquitination. The decrement in Tau induced by TH006 could decrease the cytotoxicity caused by Aβ. Furthermore, TH006 could regulate the Tau level in the brain of an AD mouse model. Therefore, partial reduction of Tau with such multifunctional peptides may open up a novel therapeutic strategy for AD treatment.