Potential Role of a Heart-Protective Protein in Alzheimer's Disease
Ling Li, PhD
University of Minnesota (Minneapolis, MN )
April 1, 2010 to March 31, 2013
Grant Reference ID:
This grant is made possible due to a generous bequest from the Trust of W. Dean Cannon, Jr.
A Novel Role of ApoA-I in Alzheimer's Disease
Emerging evidence indicates that Alzheimer's disease and cardiovascular disease share common risk factors and pathogenic mechanisms. Human apoA-I is a major cardio-protective protein but its role in the brain pertinent to Alzheimer's disease has not been defined. This study will use a combination of behavioral, biochemical, and electrophysiological approaches to investigate the role of human apoA-I in the development of Alzheimer's disease-like behavior and neuropathology in a mouse model of Alzheimer's disease.
To date, there is no cure for Alzheimer's disease. Emerging evidence indicates that Alzheimer's disease and heart disease are closely connected and may respond to common therapies. Human apolipoprotein (apo) A-I is a major heart-protective protein but its role in the brain pertinent to Alzheimer's disease has not been studied thoroughly. Several lines of evidence suggest that human apoA-I may have anti-Alzheimer's disease effects. However, the underlying mechanisms for such effects are not clear. This research project will address this issue by investigating the potential role of human apoA-I in the development of Alzheimer's disease-like symptoms in an animal model of Alzheimer's disease. The researchers will use genetically modified mice that carry human genes with Alzheimer's disease mutations and develop memory deficits and brain lesions during aging. By breeding the Alzheimer's disease mice with mice carrying the gene for human apoA-I, the researchers will produce Alzheimer's disease mice with a high level of human apoA-I in the blood circulation. With these mice, the researchers will: 1) determine the effects of human apoA-I on Alzheimer's disease-like symptoms at different stages of disease development and 2) determine the direct effect of human apoA-I on the properties of neuronal cells responsible for memory formation and storage. Results from these studies will not only provide insights into the biological role of apoA-I in the brain but also may lead to the development of novel therapies for fighting against Alzheimer's disease.
High levels of circulating high density lipoprotein (HDL), so called "good cholesterol", and its main protein, apolipoprotein A-I (apoA-I), reduce the risk of cardiovascular disease. Clinical studies show that plasma HDL cholesterol and apoA-I levels are low in patients with Alzheimer's disease (AD). To investigate if increasing plasma apoA-I/HDL levels helps to reduce AD-like memory deficits and amyloid deposition in the brain, Dr. Li’s team generated a type of mouse that has a high risk to develop AD-like symptoms, but also has an elevated level of plasma HDL/apoA-I. In this study, the team shows that whereas the mice with a regular level of plasma HDL/apoA-I develop age-related learning and memory deficits, the mice with a high level of HDL/apoA-I continue to perform normally during aging. Interestingly, there was no significant difference in the total amyloid lesions in the brain of mice with high or low levels of HDL/apoA-I. However, the team found that there was less amyloid deposition in the blood vessels and less inflammation in the brain of the mice that have high levels of HDL/apoA-I. These findings suggest that elevating plasma apoA-I/HDL levels may be an effective approach to preserve cognitive function in patients with AD. Future research will explore the potential of raising the level and quality of apoA-I/HDL pharmacologically as a preventative and/or therapeutic strategy to combat AD.
Akhter H, Katre A, Li L, Liu X, Liu RM. (2011) Therapeutic potential and anti-amyloidosis mechanisms of tert-butylhydroquinone for Alzheimer's disease. J Alzheimers Dis 26(4):767-78.
Lewis T, Cao D, Lu H, Mans RA, Su YR, Jungbauer L, Linton MF, Fazio S, LaDu MJ, Li L. (2010) Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer's disease. J Biol Chem 285, 36958-68.
First published on: Monday, April 5, 2010
Last modified on: Thursday, March 21, 2013