Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide. In spite of millions of patients with this disease it remains unclear why only a subset of elderly patients develop senile plaques and neurofibrillary tangles that are hallmarks of AD. Understanding the basic biological mechanisms that govern those differences is crucial in developing effective therapeutics to stave off disease progression. AD acutely affects synapse formation and loss of synapses is highly correlated with disease progression. The amyloid hypothesis suggests amyloid-beta (A?) as the primary component of senile plaques leads to synaptotoxicity, the loss of synapses and eventually neuronal cell death. Specifically, it is hypothesized that high-molecular weight A? oligomers (A?o) produced in the brains of AD patients are the trigger in AD pathophysiology. Previous studies show A?o derived from AD patients can bind the cellular-Prion protein (PrPC) with high affinity and initiate a signaling cascade that leads to synapse loss, cognitive decline, and even cell death, all symptoms of synaptotoxicity. Our preliminary data suggests a novel component of the A?o-PrPC signaling pathway, Proline-rich Tyrosine Kinase II (Pyk2, CAK?, PTK2B), that potentially mediates synaptotoxicity in AD. Here we propose elucidating the role of Pyk2 in AD using a genetic and pharmacological approach.
Aim 1 will investigate Pyk2 function in mediating biochemical and anatomical deficits in AD. Experiment 1a will test the hypothesis that deletion and inhibition of Pyk2 will rescue activation of A?o-PrPC signaling pathway. Experiment 1b will test the hypothesis that deletion and inhibition of Pyk2 will rescue synapse density.
Aim 2 will Investigate Pyk2 function in mediating learning and memory phenotypes in AD mouse model. Experiment 2a will test the hypothesis that deletion and inhibition of Pyk2 will rescue A??-dependent deficits in long-term potentiation (LTP). Experiment 2b will test the hypothesis that deletion and inhibition of Pyk2 will rescue Morris Water Maze (MWM) deficit in AD mouse model. Evidence suggests A?o-PrPC is important for mediating synaptotoxicity in murine models of familial-AD. Nevertheless, it remains unclear exactly how this signaling mediates the synapse loss and neuronal dysfunction observed in AD and whether Pyk2 plays a role. Our proposed research will help elucidate the biological mechanisms that mediate neuronal dysfunction and potentially identify a new therapeutic target for the treatment of Alzheimer's disease.
Alzheimer's disease is an age-dependent neurodegenerative disorder and understanding the basic biological mechanisms that lead to the pathophysiology of the disease are of ultimate importance in developing therapeutics to inhibit the progression of this disease. Although a growing body of evidence suggests that amyloid-? oligomers (A?o) serve as the trigger in AD, it remains unclear exactly how this insult leads to neuronal dysfunction. This study will aim to elucidate the role of Proline-rich Tyrosine Kinase II (Pyk2, CAK?, PTK2B) as a novel signaling mechanisms in mediating A?o signaling and how it contributes to neuronal dysfunction in Alzheimer's disease.
