All ETDs from UAB

Advisory Committee Chair

Ling Lis

Advisory Committee Members

Selvarangan Ponnazhagan

Janusz Kabarowski

Lori Mamahon-Wakefield

Jianhua Zhang

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


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.



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.