Date of Award

January 2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Colin K. Combs

Abstract

Amyloid precursor protein (APP) derived amyloid beta peptides have been extensively investigated in Alzheimer's disease pathology of the brain. However, the function of full length APP in the central nervous system remains unclear. Even less is known about the behavior of this ubiquitously expressed protein and it metabolites outside of the central nervous system. Therefore, we sought to broaden our understanding of the expression and function of APP and its proteolytic fragments in specific non-neuronal tissues. Although the majority of research effort is currently focused on neuronal amyloid beta production and its effects on cells, prior work in our lab demonstrated a novel role for APP in regulating the phenotype of monocytic lineage cells. Therefore, we hypothesized that APP can behave as a proinflammatory receptor on these cells involved in modulating their tissue infiltration and differentiation. Based upon the fact that midlife obesity is a risk factor for Alzheimer's disease and both obese adipose tissue and Alzheimer's disease brains share a common presence of increased, reactive macrophage and microglia, respectively, we hypothesized that APP may have a common role in both diseases regulating the infiltration or proinflammatory activation of microglia and macrophage characterizing both diseases. Indeed, recent data has demonstrated that APP levels are increased in adipose tissue from obese versus control individuals. To test this idea we utilized a high fat diet feeding paradigm on both C57BL6 wild type and APP-/- mice to examine any role for APP and high fat diet dependent changes in adipose tissue, brain, and intestine. In vivo changes were compared to those obtained using primary cells isolated from the murine models. Collectively, these data suggest that APP does regulate microglia and macrophage phenotype in a manner responsible for altering their behavior in tissue specific fashion. This suggests that immune-related functions of APP may be a common type of pathophysiology linking the complex diseases of obesity and Alzheimer's disease.

Download

Share

COinS