| The epsilon4 allele of apolipoprotein E is now a well-known risk factor for Alzheimer's disease, however there is still much to be learned of the physiology of apoE in the brain, throughout normal aging and AD. To better understand the neurobiology of apoE, the work included in this thesis has focused on some of the key relationships apoE holds with some proteins known or suggested to have a role in the etiology of Alzheimer's disease. The H2 allele of apolipoprotein C-I is associated with Alzheimer's disease (AD). To examine the possibility of a direct role for apoC-I in AD, we compared apoC-I and apoE protein and mRNA levels in post-mortem specimens of frontal cortex and hippocampus from AD patients with levels in non-demented controls. We were able to confirm apoC-I expression in the CNS and identify astrocytes as the source of apoC-I. In addition, we revealed differences in apoC-I expression based on location in the brain, genotype and disease status that may reflect a role for apoC-I in the pathogenesis of AD. Lipoproteins are only efficient if able to access their target cells. ApoER2 is one of the major receptors for ApoE in the brain, and has been shown to be involved not only in lipoprotein endocytosis, but also in various cellular functions such as signalling and cellular guidance. By performing an entorhinal cortex lesion, a model of synaptic plasticity, in mice which express a decreasing number of copies of the apoER2 gene, we investigated the implication of a deficiency of this particular receptor in response to damage. Our results clearly indicate a role for apoER2 in maintaining efficient synaptic plasticity. We have also used the same synaptic plasticity model to compare the reactivity of various proteins associated with Alzheimer's disease, in wild-type C57Bl/6J and apoE-knockout mice. Along with quantifiying the levels of these proteins (APP, amyloid peptides and apoE receptors LRP and apoER2), our results also show that these apoE receptors participate in synaptogenic processes in an apoE-independent fashion, supporting a role in cellular regulation mechanisms for LDL receptors. Taken together, these results further characterize the relationship between apoE and its interacting proteins and clearly demonstrate that there is not a single element causing the onset and progression of Alzheimer's disease, but rather a cascade of events that are inter-connected. |
