Developing a bispecific Amyloid β and Tau aggregation inhibitor

For most societies dementia is becoming a major health burden with 50 million annual cases of Alzheimer’s disease (AD) recorded worldwide. A cure for AD and related forms of dementia is thus lacking, and current treatments are limited to modest symptomatic relief. Amyloid-β (Aβ42) and Tau are the two hallmark proteins in AD. Although both Aβ42 and Tau have been extensively studied with regard to their individual mechanisms of neuronal toxicity, a new light has recently been shed on their possible interactions and cooperative effects in AD. We have previously developed a non-self-aggregating Aβ42 variant (Aβ42_DM), which was used as an inhibitor for Aβ42 aggregation and neurotoxicity. Aβ42_DM was able to bind tightly to its wild-type Aβ42 target, and showed a significant inhibition of Aβ42 aggregation and toxicity. Following a study that showed that Aβ42 may bind to multiple Tau-derived peptides, we followed this concept and were able to show that Aβ42_DM also inhibits the Tau-derived peptide, PHF6. This result was further validated using transmission electron microscopy (TEM) experiment where a significant reduction in PHF6 fibril formation was observed Aβ42_DM treated PHF6 samples in comparison to untreated PHF6. By co-transfecting SH-5YSY with Aβ42_DM and the neurotoxic Tau K174Q mutant, a decrease in Tau K174Q aggregates, was observed relative to cells transfected with Tau K174Q alone. In addition, an increase of ~25% viability in these cells was observed upon Aβ42_DM treatment relative to cells expressing the Tau K174Q mutant alone. This stresses the protective role Aβ42_DM has not only in Aβ42 inhibition but also in abolishing Tau K174Q neurotoxic effect.