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Title

CD2AP Regulates The Migration of Plasmacytoid and Conventional Dendritic Cells and CD2AP Involvement in Amyloid Precursor Protein Trafficking is Linked to Neuronal Toxicity

Date of Award

Summer 8-15-2012

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

CD2-associated protein (CD2AP) is implicated in diverse biological functions, including regulation of actin cytoskeleton dynamics and coordination of vesicular trafficking. Yet, despite its involvement in these processes, its precise function in vivo is still poorly understood.

Recently, we observed that CD2AP is highly expressed in dendritic cells (DCs). DCs provide a critical link between the innate and adaptive immune system. Upon recognizing foreign antigen, DCs undergo a maturation program that results in the secretion of cytokines, and their subsequent migration to lymph nodes to present the antigen to naïve T cells. Both these processes are crucial steps in engaging the adaptive immune response and are dependent on proper vesicular trafficking and actin cytoskeleton remodeling. Therefore, we decided to examine whether CD2AP is required for either or both of these functions.

We began our studies by first demonstrating that CD2AP is not required for the development of two major DC subsets - plasmacytoid DCs (pDCs) and conventional DCs (cDCs). In addition, we found no defects in the secretion of proinflammatory cytokines by both DC subsets, and no defects in type I IFN production, which is a major and defining function of pDCs. Since CD2AP is implicated in actin regulation, we studied migration of pDCs and cDCs to lymph nodes in inflammation/activation models. Surprisingly, we got very different results with the two DC subsets. The CD2AP knockout pDCs displayed dramatically reduced migration, while the cDCs showed enhanced migration. We are currently working out potential mechanisms to explain these intriguing results.

Recent genome-wide association studies (GWAS) have implicated CD2AP as an Alzheimer's disease susceptibility locus. Therefore, we sought to address whether the involvement of CD2AP in Alzheimer's disease is at the level of regulating the trafficking of amyloid precursor protein (APP) and the production and/or secretion of beta-amyloid peptides. We determined that CD2AP deficiency in the context of APP overexpression in neuronal cells resulted in significant cell death. This defect correlated with decreased secretion and increased intracellular retention of beta-amyloid peptides. Beta-amyloid peptides aggregate at acidic pH and form cytotoxic fibrils. We are presently trying to determine if beta-amyloid peptides are either misdirected to or retained within a particular compartment/pathway. Our current studies point to CD2AP being involved in the endosomal recycling pathway.

Language

English (en)

Chair and Committee

Andrey S Shaw

Committee Members

Gregory D Longmore, Marina Cella, Barry P Sleckman, John A Cooper, Paul M Allen

Comments

Permanent URL: https://doi.org/10.7936/K7ZP441F

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