While natively unfolded, the MTBR tandem repeat region (3R/4R) can undergo tau-tau binding resulting in the paired helical filaments seen in NFTs, forming a cross-β structure similar to that seen in amyloid plaques. [73] Methylene blue (MB) is a small molecule phenothiazine initially developed in the late 1800s for treatment of malaria and still used in modern medicine. In 1996, MB was found to disrupt these high affinity tau-tau bonds, preventing aggregation. [74] MB was then tested in P301S and TauΔK transgenic mice, where it was found to decrease phosphorylated tau aggregates and rescue memory deficits, though only when given prior to symptom onset. [75,76] Later studies posited an increase in clearance via upregulation of autophagy as a potential mechanism for the benefits seen in mouse models [77].
