The apolipoprotein E (apoE) ɛ4 is a risk factor for AD. The mechanism by which apoE ɛ4 confers such a susceptibility to AD is unknown. We explored whether low levels of apoE may mediate the processes leading to neurodegeneration and cognitive decline in AD by using apoE knockout mice (apoEKO). The complementary hypothesis was also tested to determine whether apoE could be used as a therapeutic target in the treatment of AD. / We examined the effect of apoE deficiency on the reparative capacity and glial response following entorhinal cortex lesion (study 1), the effect of age and apoE deficiency on the integrity of the circuitry underlying hippocampal-dependent cognitive functioning in apoEKO mice (3 and 12 month-old) (study 2). Given that enhanced sensitivity to stress and/or anxiety can interfere with cognitive functioning, we assessed behavioral anxiety in apoEKO mice (12 month-old) using a battery of tests with varying degree of aversiveness and novelty (study 3). The forth study assessed the effect of pharmacological induction of apoE on alterations typically associated with age such as synaptic loss and glial reactivity in aged rats (26 month old) using Probucol. / The results revealed that apoE deficiency is associated with an altered pattern of glial reactivity that coincided with impaired sprouting responses, and with behavioral impairments (hippocampal-dependent procedural deficit and enhanced susceptibility to stress and anxiety) that mimic some aspects of the clinical phenotype of AD patients. Furthermore, chronic Probucol treatment in rats led to significant increases in apoE and its receptor the low density lipoprotein related protein receptor (LRP). In parallel, were increases in the synaptic marker SNAP-25 along with a drastic attenuation of the age-related astroglial reactivity. / The findings show that apoE plays an important role in the repair processes and its induction by Probucol could promote synaptic plasticity to counteract the synaptic deterioration and glial activation associated with age or damage. These findings are consistent with the hypothesis that part of the risk of developing AD may be related to low levels of apoE, and suggest a novel therapy for the treatment of AD based on apoE neurobiology.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.82841 |
| Date | January 2002 |
| Creators | Champagne, Danielle |
| Contributors | Poirier, Judes (advisor), Rochford, Joseph (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 (Division of Neuroscience.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001973944, proquestno: AAINQ88436, Theses scanned by UMI/ProQuest. |
Page generated in 0.0018 seconds