Mechanisms of apoE mediated risk in Alzheimer's disease: Aβ peptide clearance and attenuation of cytotoxicity by apoE isoforms

[Truncated abstract] Alzheimer’s disease (AD) is currently recognised to be the most common form of dementia. It is predominantly sporadic and histologically characterised by the presence of plaques and tangles in the brain. The major protein component of the plaques is amyloid-β (Aβ), a small peptide whose function is poorly understood. This protein is thought to play a key role in the pathogenesis of AD, however many gaps exist in our knowledge of its mechanisms of action. The interaction of risk factors in the development of AD are also poorly understood, due to its multifactorial nature. However one of these risk factors, the APOE gene, has been implicated in the majority of cases and is considered the major genetic risk factor for AD. In humans, there are three main alleles of APOE, namely ε2, ε3 and ε4. Of these alleles, carriage of ε4 has been associated with the greatest risk of developing AD. These alleles code for apolipoprotein E (apoE), a polymorphic glycoprotein and key ligand to the physiology of lipid homeostasis and more recently, it has been linked to the physiology of Aβ. The mechanisms by which apoE imparts the increased risk for AD are not well understood. I investigated the isoform specific effects of apoE on the reduction of Aβ cytotoxicity. Treatment of cells with Aβ42 and phospholipid associated apoE isoforms showed differential attenuation of Aβ42 cytotoxicity of the order E2>E3>E4. The differential effects were reflected by differences in the protein profiles of neuroblastoma cells in response to Aβ42 and apoE isoforms.