Alzheimer's disease (AD) is characterized by a devastating and progressive loss of memory and cognitive function. This decline is closely related to selective degeneration and death of hippocampal and neocortical neurons. Recently, the epsilon4 allele of the gene for apolipoprotein E (apoE, protein; APO, gene) has been recognized as a genetic susceptibility factor in late onset AD. The actual protein apoE is present in many of ht pathological lesions of AD. However, the relationship of apoE to the pathogenesis of cell injury and death in AD remains to be clarified. One possibility is that apoE has an isoform-specific, direct effect on intraneuronal metabolism. For this to be the case. (1) apoE must be present in neurons: (2) since neurons do not synthesize apoE. cells that synthesize the protein must be located near the neurons and apoE must have a way of getting into neurons: (3) there must be a clear set of conditions under which a neuron will take up apoE. In order to investigate these factors, we will carry out the following specific aims in human hippocampus and temporal cortex from controls. AD patients, and surgical specimens from temporal lobe epilepsy patients: (1) Characterize apoE-containing human cortical neurons to provide information for the hypothesis that apoE uptake by human cortical neurons is a normal neuronal response to remodelling and repair, but confers age- and APOE- isoform specific risk for AD; and (2) Characterize relationship of type and location of apoE-containing glial cells and neuronal expression of alpha2- macroglobulin receptor to neuronal apoE uptake to test the hypothesis that apoE uptake by human cortical neurons depends on expression of 'apoE'receptors and the presence of nearby glial cells secreting apoE. These experiments will be carried out using specific immunocytochemistry for apoE and other relevant markers and comparing this to traditional markers of AD pathology. Using the same methodology, we will also investigate as a third specific aim (3) immunolocalization of apoE and its receptors in transgenic rodents containing the three major APOE alleles - APE alleles - APE2, APOE3, and APOE4. These experiments should both further our understanding of which classes of neurons that are particularly vulnerable to AD pathology and elucidate the role apolipoprotein E may play in that vulnerability. This information will assist in the evaluation and development of treatments to protect neocortical and hippocampal neurons from the devastating effects of AD.