Apolipoprotein E and Alzheimer Disease The apo-e4 allele of apolipoprotein E has recently been found to be in striking genetic disequilibrium with the development of Alzheimer's disease (AD) in patients with late onset familial AD (Strittmatter et al., 1993). This observation has been extended by our own data and at least 4 independent groups to show that apo-e4 is found at a much higher than expected frequency in sporadic AD as well, and apo-E4 has accordingly been suggested to be an heritable risk factor for AD. Neuroanatomical, biochemical and molecular biological tools will be used to gain insight into the biological factors that mediate this increased risk. The results suggest one of two possibilities: either the apo-E4 protein interacts with pathophysiological processes to affect the course or likelihood of AD, or the apo-e4 allele is a genetic marker suggesting the presence of a causative or susceptibility factor nearby. Both possibilities will be explored; emerging evidence of biological interactions between apo-E and AB, a molecule firmly established as playing a role in AD, favors the first possibility. The working model is that apo-E binds AB in the neuropil, and transports it to apo-E receptors that are linked to clathrin coated pits for subsequent metabolism. The investigator hypothesizes that apo-E4 protein performs this """"""""clearing"""""""" function less well than apo-E3. Already preliminary data support key features of this model: The investigator has confirmed genetic disequilibrium of apo-E4 and AD in an autopsy confirmed population of sporadic AD. The investigator also found that the amount of AB deposition is related to apo-E genotype, increasing from 3/3 to 3/4 to 4/4. Apo-E immunostains senile plaques (SP) in AD brains. Low density lipoprotein receptor related protein (LRP) immunostaining colocalizes with apo-E on SP, placing this apo-E receptor in close proximity to AB and apo-E. The investigator has developed in vitro models to study these interactions. Using ligand blots they have found specific and high affinity binding of AB to apo-E with Kd in the 10-20 Nm range. Furthermore, they have preliminary data using fibroblasts that express a high amount of LRP support the idea of cellular uptake of AB complexes in vitro. The investigator will characterize this uptake and study the cellular consequences and metabolism of AB. The application has 3 major aims: (1) to investigate the anatomical relationship among apo-E, its receptors, and AB deposition in AD brain tissue; (2) to investigate the interaction of AB with apo-E3 and apo-E4 in vitro. Determine if apo-E facilitates AB uptake or binding to cells in culture via LRP or other members of the LDL receptor family; and (3) to test the hypothesis that amount of apo-E4 expression is related to degree of Alzheimer neuropathological change or risk for dementia. These experiments will study the role apo-E and its receptors play in the pathophysiology of AD, and explore biological mechanisms that may underlie the increased risk for AD mediated by apo-e4.
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