Using small molecules that cross the blood brain barrier is an attractive approach. Thus far the compounds tested have clear limitations include off-target effects specially for kinase inhibitors. Examples include studies on lithium and valproate, which have action on kinases in the CNS but also involve other diverse mechanisms, which led to side effects such as the toxicity seen in the valproate trials. Even approaches where the mechanism is limited to a single kinase will likely lead to a pleotropic effect given the complexity of cell signaling, though the sum total of this effect may be beneficial. Recently published studies revealing the Cryo-EM structure of tau aggregates provide valuable knowledge of the atomic coordinates of tau filaments. [24] The structural information of tau aggregates could be helpful in rational design of specific tau aggregation inhibitors. These structures are also useful for the design of tau binders that can be used as part of the PROteolysis TArgeting Chimeras (PROTACs) approach. PROTACs is a strategy to degrade proteins by hijacking the ubiquitin-proteasome system (UPS). PROTAC is a bifunctional-hybrid molecule that on one
