Alzheimer's disease (AD) is the most important cause of dementia, but the mechanism of pathogenesis remains unknown. The epsilon4 allele of apolipoprotein E (apoE) has been confirmed as the most important genetic risk factor for most cases of AD and is associated with Abeta-containing senile plaques, one of the neuropathological hallmarks of AD. We determined the neuronal binding, internalization and degradation of human apoE isoforms apoE3 and apoE4 in the presence and absence of Abeta peptides using primary hippocampal neurons from rat. The findings demonstrate apoE binding and internalization in neurons without endogenous synthesis. Increased apoE3 degradation was observed relative to the apoE4 isoform. Lipophilic Abeta peptides increased apoE binding to hippocampal neurons; the increase was greater for the apoE4 isoform than for the apoE3 isoform. Abeta uptake by hippocampal neurons was increased in the presence of apoE, more so in the presence of the apoE4 than apoE3 isoform. Further, apoE was shown to reduce the extracellular level of Abeta in hippocampal cultures. We also find that all three major apoE isoforms were equally potent inhibitors of Abeta fibril formation, which is thought to be necessary for in vitro neurotoxicity and possibly the neuronal degeneration observed in AD. Further, when apoE was associated with cholesterol-containing liposomes or very low density lipoproteins, its ability to prevent Abeta fibril formation was diminished. In two brain regions affected by AD neuropathology, the hippocampus and frontal cortex, apoE levels were found to be decreased while Abeta levels were increased. Levels of apoE and Abeta1--40 were found to be apoE genotype dependent, with lowest levels of apoE and highest levels of Abeta occurring in epsilon4 allele carriers, suggesting that a reduction in apoE levels may give rise to increased deposition of amyloid peptides in AD brain. The low density lipoprotein receptor-related protein, an important neuronal ap
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35979 |
| Date | January 1999 |
| Creators | Beffert, Uwe. |
| Contributors | Poirier, Judes (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Neurology and Neurosurgery.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001681265, proquestno: NQ55300, Theses scanned by UMI/ProQuest. |
Page generated in 0.0022 seconds