Novel Kinase Target in Alzheimer's Disease

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ABSTRACT Alzheimer’s disease (AD) is the most common type of dementia in the world and one of the main causes of death. There are currently no FDA approved drugs for AD patients that significantly improve disease symptoms or are curative. Autophagy modulating agents are emerging as promising therapies for AD. Reports using mouse models with dysfunction of AD-associated proteins such as Aβ, Aβ precursor protein (APP), presenilin 1 (PS1), and tau, show that promoting autophagy alleviates AD symptoms including improvement of cognitive dysfunction in the hippocampus and a reduction in protein aggregation. However, a problem persists where clinically relevant pharmacological agents to target enzymes that regulate autophagy, such as kinases, and have efficacy toward AD are lacking. Furthermore, the study of autophagy in AD is hampered by the need to delineate the signaling pathways that are tractable to evaluate the effect of autophagy modulation during disease progression. We propose to address these problems by studying a protein kinase called HUNK that is an autophagy promoting factor and has not been previously evaluated in AD. Our data shows that HUNK is downregulated in the hippocampi of human AD patient samples. Our findings also show that HUNK expression in the hippocampus of 5XFAD mice is reduced compared to age-matched non-diseased mice. Cognition deficits in AD patients include impairments in both spatial memory, primarily mediated by dorsal hippocampus (dHip), and emotional and motivated behaviors, which are primarily regulated by ventral hippocampus (vHip). Autophagy is linked to these cognitive deficits. Furthermore, we have recently identified a pharmacological agent that induces HUNK enzymatic activity. From a pharmacological perspective, modulation of HUNK is promising because neither mice engineered to transgenically overexpress Hunk nor mice with germline deletion of Hunk have any significant developmental or disease related defects. Consequently, methods to increase HUNK activity could be applied to improve treatment of AD. Our goal with these studies is to test activation of HUNK and its subsequent effect on AD-related pathology and cognitive dysfunction. These studies will allow us to determine whether HUNK is a druggable target for intervention in AD. Until now, HUNK has not been studied extensively in brain, and we are proposing to test a novel HUNK pharmacological agent for application to AD, making these studies highly innovative. The overarching hypothesis of this grant is that HUNK declines in ventral (v) Hip and dorsal (d) Hip of AD brains, leading to AD pathology and impairments in both spatial memory and motivation behaviors. Methods to induce HUNK activity are hypothesized to reverse AD-associated dysfunction and cognitive decline.