Date of Award

2015

Document Type

Thesis

Department

Chemistry

First Advisor

Dr. Joe Jeffers

Second Advisor

Dr. Jay Curlin

Third Advisor

Dr. Lori Hensley

Abstract

The primary genetic risk determinant for late-onset Alzheimer's disease is the apolipoprotein E gene (APOE). Variations in this gene produce three different isoforms of the apolipoprotein E protein (ApoE): ApoE2, ApoE3, and ApoE4. ApoE# is the most common isoform, so rates of LOAD among other genotypes are indexed to this variant. ApoE2 is rather rare, but its carriers are less likely to get LOAD; when they do, they get it later. The second most common variant is ApoE4, and its carriers are significantly more likely to get LOAD. They also tend to succumb earlier. Once developed, LOAD is characterized by inflammation-related (M1) changes in microglia, non-neuronal cells that mediate innate immunity in the central nervous system (CNS). Microglia are also capable of expressing gene products associated with an alternative, non-inflammatory (M2) form of activation in the periphery, but the degree to which microglia recapitulate those peripheral phenomena and the influence of LOAD etiology in the M1-M2 spectrum remain to be determined. Thus, identifying the effects of ApoE3 and ApoE4 on activated microglia could be helpful in two important ways: 1) by elucidating the differences in activity between ApoE3 and ApoE4 during LOAD and 2) by characterizing the M1-M2 spectrum of activation in the CNS. To explore these areas, we cultured primary microglia harvested from neonatal rats and treated them with ApoE3, ApoE4, an M2 activator---interleukin-4--- or combinations thereof. We then measured expression of M2 genes, phagocytic activity, and mitochondrail respiration. Preliminary results have shown substantial effects of ApoE and IL-4 on all these parameters, notably, epression of CD33 and TREM2, modulators of phagocytic activity, and other genetic determinants of LOAD risk. Ongoing experiments seek to further characterize these effects.

 
 

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