- To define common and newly designed apoE isoforms and domains involved in the interaction with its ligands.
- To produce these apoE isoforms in large quantities.
- To identify and characterize the interaction of these apoE isoforms with known and novel protein ligands in vitro and in vivo.
- To generate transgenic mice carrying genes that code for these apoE isoforms and amyloid precursor protein.
- To characterize these mice with respect to the development of atherosclerosis and Alzheimer's Disease.

By using interdisciplinary approaches, this project aims to study systematically how alterations in the structure of apoE affect its functions which lead to human disease. Special emphasis will be placed on the role of apoE in the pathogenesis of atherosclerosis and Alzheimer's Disease. Alteration in apoE which changes its interactions with lipoprotein receptors, the secreted proteins such as amyloid peptide b (Ab) or intracellular proteins (such as tau and other protein ligands) in the brain may lead to atherosclerosis and Alzheimer's Disease, respectively. Our knowledge on domains of apoE which are required for the binding of apoE to these receptors and other proteins are largely unknown.

Understanding the molecular mechanisms and pathophysiology of diseases caused by apoE mutations may provide effective intervention for the prevention of coronary heart diseases (CHD). In addition, variations at the apoE gene locus affects the risk for Alzheimer's disease (AD), the most common cause of dementia. Presently, no effective treatment for AD is known. Such treatment may become possible if we understand the molecular interactions between apoE and its intracellular or secreted protein ligands present in the brain. The major emphasis of this project will be placed on how the abnormal interactions of apoE with its ligands (Ab, tau, and other apoE ligands) and LRP contribute on the role of apoE in the pathogenesis of atherosclerosis and AD. This project will provide new insights on how genetic alteration may lead to age related neurodegenerative diseases (area 4.4), as well as to cardiovascular diseases (area 4.3) and may provide rational approaches towards the treatment of these conditions.