The aberrant accumulation of tau protein is associated with neurodegeneration and cognitive decline in Alzheimer’s disease (AD). These toxic aggregates form when tau is abnormally phosphorylated (or tagged) by enzymes known as kinases. New treatments that target overactive kinase activity and abnormal phosphorylation of tau and other AD-related proteins, could have direct therapeutic benefit for AD patients. Dr. Dunckley and colleagues have developed two novel compounds to inhibit DYRK1A, a kinase that phosphorylates tau, as well as AD-related amyloid precursor protein (APP) and presenilin 1. Preliminary data from Dr. Dunckley’s lab indicates that DYRK1A inhibitors reduce phosphorylated tau levels in the brain without overt toxicity. The goal of this project is to assess whether DYRK1A inhibitors delay cognitive decline and the onset of Alzheimer’s-related pathology in a well-characterized AD mouse model that displays abnormal tau and amyloid pathologies.  If successful, the proposed studies will provide critical data to advance one of these drug candidates toward human testing.

The additional proposed studies by the Harrington expert consultants are to helping the project meet the necessary milestones, demonstrate the value of DRYK1A as a target, and secure a future licensing partner.