. Alzheimer?s disease (AD) is the most prevalent neurodegenerative disease of the elderly. The complement cascade, a powerful effector mechanism of the innate immune system that can be directly activated by fibrillar A?, is implicated as a player in this inflammatory scenario. In brain, expression of most complement components increases during aging and further increases in AD patients and animal models of AD, consistent with a role for complement immune activation in progression of the disease. Complement activation fragment C5a has been a major focus, as inhibition of its proinflammatory receptor, C5aR1, leads to less activation of microglia and astrocytes, preservation of neuronal complexity and reduction of cognitive loss in AD models. These critical observations strongly suggest C5a binding to its receptor C5aR1 initiates cellular activation leading to changes in protein expression in microglia and astrocytes, which result in pathological phenotypes and disease progression. The primary goal of this proposal is to systemically understand alterations in cell-specific protein expression that result from signaling via C5a-C5aR1 in the context of Alzheimer?s disease. Specifically, this will extend our knowledge of induction of specific RNAs to production of the proteins, and the contribution of each cell type to those functional proteins, that ultimately accelerate pathogenesis and neuronal dysfunction in Alzheimer?s disease models.
. The goal of this proposal is to develop methods for cell-specific proteome labeling in the living mouse brain. We aim to utilize these technologies to understand the role of complement signaling in Alzheimer?s disease and how cell-specific protein expression is altered.
