Tau-Targeted PROTACs Degrade Pathology-Associated Tau and Improve Memory in Alzheimer's Disease Models.
Tau aggregation and hyperphosphorylation are key pathological features of Alzheimer's disease (AD). Because Tau is intrinsically disordered, conventional small-molecule inhibitors have achieved limited success. Proteolysis-targeting chimeras (PROTACs) enable the targeted proteasomal degradation of previously considered undruggable proteins. We designed Tau-targeted PROTAC candidates using methylene blue (MB) as a recognition moiety for aggregation-prone motifs within the microtubule-binding region and varied the linker lengths and E3 ligase recruitment ligands to optimize degradation efficiency. Cell-based screening revealed that MB-2-VHL1 and MB-2-VHL2 are active degraders. In vivo studies confirmed a reduction in total Tau levels and degradation of phosphorylated Tau (p-Tau). In 3xTg-AD mice, subcutaneous administration of MB-2-VHL2 was associated with reduced hippocampal Tau and p-Tau levels and improved recognition memory and spatial learning. MB-2-VHL2 was also detectable in both serum and brain tissue by LC-MS/MS after subcutaneous administration and did not cause detectable histological or biochemical toxicity. These results indicate that MB-2-VHL2 can reduce both total Tau and p-Tau levels in vivo. Although the reduction in p-Tau appeared more pronounced under our experimental conditions, whether MB-2-VHL2 preferentially targets pathological Tau remains to be determined. Overall, these findings support further optimization and preclinical evaluation of Tau-targeted PROTACs as a potential therapeutic strategy for AD.