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Drs. Woo Shik Shin and Christine Crish (Pharmaceutical Sciences, NEOMED)

Developing Combination Therapies for Amyloid beta-dependent and -independent tau aggregation

Alzheimer's Disease (AD) is the leading form of dementia in the US, with ~1 million new cases diagnosed each year and >6 million Americans currently suffering from this disease. The high failure rate in clinical trials for diseases has been suggested to stem from an incomplete understanding of the fundamental molecular mechanisms underlying AD pathology. Recent research has increasingly revealed the significant role of tau proteins and their pathological aggregates in the interaction and binding with amyloid-β (Aβ). This highlights efforts to elucidate the two potential tau aggregation mechanisms implicated in AD, the Aβ-independent and the Aβ-dependent pathway, suggesting pathological possibilities.

Here, we will investigate an alternative approach and determine the impact that targeting direct (Aβ-independent) and indirect (Aβ-dependent) tau aggregation can have on cognitive function in disease model mice. Using a computational screening approach, we have identified several potent, plant-based flavonoids capable of both inhibiting tau protein aggregation as well as disassembling existing tau fibrils. Our pilot study has revealed that, through our drug repurposing strategy, we can effectively block an additional target pathway by safely and successfully inhibiting the LiIrB2, which is reported as one of the representative receptors for Aβ. In this project, we will investigate and develop a novel combination anti-tau therapy that targets both aggregation pathways to significantly reduce Aβ oligomer uptake, decrease aggregate potentiation, inhibit the formation of tau aggregates, and potential dissemble existing fibrils in order to prevent disease progression in both early and advanced stage AD mouse models. The successful initial accomplishment of these goals will represent a significant step forward in the identification and development of new treatment modalities for AD. Additionally, the repurposing and using safe and approved drugs will significantly accelerate the path toward clinical investigation.