Proof of concept for the therapeutic potential of alpha B-crystallin in PSP has been obtained in a transgenic mouse model. In mice carrying the gene for the mutant tau P301S protein, tau aggregates gradually form over the course of several months. Largely by triggering a pro-inflammatory response by microglia, these aggregates eventually cause neurons in the outer cortical layers to die, leading to the loss of about 1/3 of all neurons in those areas after 3 months. Infusion of alpha B-crystallin into the brains of these mice almost completely prevents this degenerative process. After treatment with alpha B-crystallin, the numbers of neurons in the outer cortical layers were restored to normal levels again. Clearly, an equivalent effect in humans would provide significant benefit to people with PSP.

Alpha B-crystallin exerts its protective effects in mouse PSP primarily by converting the pro-inflammatory state of microglia into a neuroprotective, beneficial state. The protein is known to do so by activating microglia via Toll-like receptor 2. Instead of producing damaging substances and causing oxidative stress, alpha B-crystallin-activated microglia produce protective factors and counteract oxidative stress. This also alleviates the driving force behind abnormal tau phosphorylation and accumulation. Furthermore, alpha B-crystallin act as a molecular chaperone, and promotes tau aggregates to dissociate into single protein molecules again. In this manner, the chronic trigger for inflammation within the CNS is removed.


Like other heat shock proteins, alpha B-crystallin acts as a molecular chaperone. In this function, it dissociates tau aggregates into free soluble protein molecules, and prevents new aggregates from being formed.