Aberrant Protein Kinase C Signaling in Alzheimer's Disease

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Summary/Abstract The overall vision of our proposed research is to understand the molecular, cellular and electrophysiological mechanisms by which aberrant signaling by protein kinase C (PKC) promotes the pathology of Alzheimer’s Disease (AD). This age-related dementia is characterized by deregulated signaling, degeneration of synapses, neuronal death and, ultimately, a reduction in the size of brain regions involved in learning and memory. While significant efforts have been devoted to understanding the role of extracellular amyloid-β (Aβ) plaques that are a hallmark of the disease, emerging evidence points to deregulated signaling by PKC isozymes playing a potentially causative role in the disease. We have assembled a team with extensive and complementary expertise in PKC mechanisms and synaptic mechanisms to understand how aberrant PKC signaling contributes to the disease phenotype. Recent searches for rare functional variants associated with AD from whole genome sequencing data from families with late-onset AD have identified highly penetrant variants in the genes for both PKC (PRKCA) and PKC (PRKCH) in multiple families that co-segregate with AD affection status. All PKC variants display enhanced activity, and our detailed analysis of one variant (PKC M489V) has established that it is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model. Enhanced PKC function driving AD pathology is consistent with unbiased phosphoproteomics analysis that have identified elevated PKC signaling as one of the earliest events in AD diseased brains. Thus, the hypothesis driving this proposal is that two PKC isozymes, PKC in neurons and PKC in microglia, play essential roles in brain homeostasis and that deregulation of either contributes to the pathology of AD. We aim to combine state-of-the-art proteomics, biochemical, imaging and electrophysiological approaches in order to study molecular mechanisms of how aberrant signaling by PKC or PKC impact neuronal or microglial function. We also will test the hypothesis that increased protein levels of either PKC is a biomarker in AD. This project should make significant strides in our understanding of neurodegeneration and AD as well as providing possible new therapeutic strategies against this devastating disease.