While amyloid-targeting therapies are the first disease-modifying treatments approved for AD, there remains a critical need for therapies that target downstream pathogenic proteins that emerge after amyloid beta deposition. Tau, the other hallmark AD protein aggregate, is a popular choice of second target. Tau is considered an encouraging target in terms of efficacy because tau more strongly correlates with neurodegeneration and cognitive decline than amyloid does. However, a persistent question in trying to prevent and treat tau remains: how does the accumulation of amyloid pathology lead to the initiation of tau pathology?
Dr. Sun has shown in previous studies that inhibiting the formation of amyloid plaques before tau formation dramatically reduced tau spread and neurodegeneration. But when the plaques were halted after the tau pathology had already begun, the inhibition was largely ineffective. Here, he aims to dig more deeply into this transition point between amyloid and tau in order to identify the key drivers that could be targeted therapeutically. To do so, Dr. Sun will use a cell-based model he developed that maintains the disease and age-related hallmarks that are often lost in other cell models.
The project has two primary experimental aims. In the first, he will compare the changes in the genes expressed by neurons with and without inhibited amyloid plaque production. This comparison will help him identify the key changes driving tau pathology that are primarily caused by amyloid. The second aim will then take the strongest candidate genes from the first aim and validate their effects on the amyloid-to-tau transition by either removing the gene in cultured neurons or by using pharmacological inhibitors in his neuronal cultures. In each case, he will test efficacy when interventions are initiated before and after the onset of amyloid pathology formation, while measuring tau pathology and neuronal death after his interventions to assess efficacy.
