Advisory Committee Chair
Ling Lis
Advisory Committee Members
Selvarangan Ponnazhagan
Janusz Kabarowski
Lori Mamahon-Wakefield
Jianhua Zhang
Document Type
Dissertation
Date of Award
2010
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoprotein (HDL) in circulation and is expressed mainly by the liver and intestine. The levels of apoA-I/HDL are inversely related to the incidence of cardiovascular disease. Because of the connections between heart disease and Alzheimer's disease (AD), it is conceivable that high levels of apoA-I/HDL may be protective against AD. However, the limited literature shows mixed results on the role of apoA-I/HDL in the development of AD. It is hypothesized that increased expression of human apoA-I will ameliorate the behavioral deficits and characteristic amyloid-ß (Aß) plaque formation in a mouse model of AD. To test this hypothesis we generated a line of triple transgenic (APP/PS1/AI) mice by breeding APP/PS1 double transgenic mice, a mouse model for AD that co-overexpresses mutant forms of amyloid precursor protein (APP) and presenillin 1 (PS1), with human apoA-I transgenic mice. APP/PS1/AI mice exhibit improved learning ability over age and sex matched APP/PS1 mice. However, there were no significant changes in ß-amyloid deposition in the brain of APP/PS1/AI mice. In contrast, it was observed that APP/PS1/AI mice have a significant reduction in cerebral amyloid angiopathy (CAA) compared to APP/PS1 mice. In addition, we observed a significant decrease in activated glial cells in APP/PS1/AI mice, which indicates a decrease in inflammation. To better understand the underlying anti-inflammatory mechanisms, in vitro methods were utilized to determine what effect increased levels of apoA-I would have in the presence of ß-amyloid. To achieve this, organotypic hippocampal slice cultures were transduced with a lentiviral vector to overexpress human apoA-I and subsequently treated with monomeric and oligomeric Aß. In addition, BV2 cells, a mouse microglial cell line, were treated with human plasma derived apoA-I as well as monomeric and oligomeric Aß. Results verify that overexpression of apoA-I by lentivirus transduction in slice culture or the addition of apoA-I in BV2 cultures reduces inflammatory cytokine/chemokine production and reduces microglial activation in the presence of Aß. Together with the data from APP/PS1/AI transgenic mice, it has been demonstrated that apoA-I ameliorates the characteristic behavioral deficits in APP/PS1 mice through a reduction in CAA and inflammation in spite of continued amyloid plaque formation.
Recommended Citation
Lewis, Terry L., "Effect of overexpressing apolipoprotein A-I in an animal model of Alzheimer's disease" (2010). All ETDs from UAB. 2259.
https://digitalcommons.library.uab.edu/etd-collection/2259