UC San Diego

As the worldwide population affected by Alzheimer’s disease (AD) and related dementia (ADRD) increases, there has been growing interest in developing therapies that target the microtubule-associated protein tau, given its close association with cognitive decline. Conventional approaches including immunotherapy with antibodies and antisense oligonucleotides have limited effectiveness due to limitations on timing and dosing of the treatment and heterogeneity of tauopathies. Building on the dysfunction of proteostasis observed in AD and other tauopathies, promoting protein degradation mechanisms to reduce tau accumulation and aggregation emerged as an alternative strategy. However, previous attempts at augmenting a single protein degradation mechanism have limited efficacy in reducing tau levels, possibly due to compensations from other non-targeted mechanisms.In this study, we reported that in neurons of the human P301S tau expressing (PS19) mouse brain and neurons derived from a V337M mutant tau expressing induced pluripotent stem cell (iPSC) culture, the nuclear speckle, an upstream master regulator of global proteostasis transcription, exhibited reduced diffuseness and impaired organization. The dysfunction of nuclear speckles in tauopathy neurons is a potential contributor to the dysfunction of downstream proteostasis mechanisms in AD and other tauopathies. We identified the rejuvenation of nuclear speckles to restore their morphology and function as a global proteostasis promotor in neurons, utilizing the FDA-approved drug pyrvinium. We showed that pyrvinium treatment restored the size and distribution of nuclear speckles in neurons, leading to the upregulation of genes associated with the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS). Consequently, pyrvinium treatment augmented autophagy and UPS activity, and decreased pathological tau levels in neurons. Our finding highlights the potential therapeutic approach of targeting nuclear speckles to promote global proteostasis in neurons, proposing pyrvinium as a novel therapeutic strategy not only for alleviating tauopathies in Alzheimer's disease, but also for addressing various other proteinopathies.