Pathophysiology of cerebral ischaemia : effects of APOE genotype on outcome and endocytosis
Apolipoprotein E (apoE denotes protein: APOE denotes gene) is a lipid-transport protein abundantly expressed in the brain and strongly upregulated after acute brain injury. The APOE e4 allele is the major genetic risk factor for Alzheimer’s disease (AD) and has been associated with poorer outcome after various types of acute brain injury, including traumatic brain injury and subarachnoid haemorrhage. However, the role of APOE genotype in focal ischaemic stroke is less clear. The mechanism(s) by which APOE genotype may modulate outcome after acute brain injury are also unclear at present. Accordingly, the studies described in this thesis were undertaken to further address these issues. 1. Endocytic pathway alterations in human temporal lobe after global cerebral ischaemia and association with APOE genotype. 2. Characterisation and validation of the intraluminal filament model of focal cerebral ischaemia in C57BI/6J mice. 3. Association between APOE genotype and differences in outcome and endocytic pathway alterations after focal cerebral ischaemia in mice. 4. Adenovirus-mediated gene transfer of APOE e3 markedly reduces ischaemic brain damage after focal cerebral ischaemia in mice. The data presented in this thesis indicate an important role for APOE genotype in modulating outcome after ischaemic brain injury, further highlighting the favourable effects associated with the APOE e3 allele. APOE genotype-dependent alterations in the endocytic pathway are mechanisms which could contribute to differences in outcome. These data also highlight the neuroprotective effects achieved by manipulating apoE levels to promote the beneficial effects of apoE3. An apoE-based therapeutic strategy may be a potential approach for treatment of ischaemic brain injury in humans.