Proceedings of The Physiological Society
King's College London (2011) Proc Physiol Soc 22, PC16
Investigation of the effects of ApoE genotype on astrocytic protein secretion
R. Abeti1, D. Hanger1
1. King's College London, London, United Kingdom.
The most significant genetic factor in Alzheimer’s disease (AD) is the increased risk of developing this disease that is conferred by possession of one or two alleles of apolipoprotein E4 (ApoE4). However, despite much research, the mechanism by which AD pathogenesis is modulated by the different ApoE isoforms (ApoE2, ApoE3 and ApoE4) remains obscure. The consequences of ApoE isoforms conferring differential susceptibility to AD include differences in (1) the ability of the various isoforms to produce or remove neurotoxic forms of amyloid beta-peptide, a constituent protein of the plaques deposited outside neurons in AD brain, and (2) sensitivity to amyloid neurotoxicity. Several studies have shown that over-expression of mutant forms of amyloid precursor protein (APP) leads to the widespread appearance of amyloid-containing deposits in the brains of transgenic mice. However, mice lacking ApoE are reported to be relatively resistant to the neurotoxic effects of amyloid beta-peptide when crossed with mice expressing mutant APP. Importantly, replacing mouse ApoE with human ApoE3 in mutant APP over-expressing mice delays the development of amyloid deposits compared to replacement with human ApoE4. Furthermore, over-expression of ApoE4 appears to exacerbate amyloid deposition in APP mutant mice. These findings indicate that ApoE may be involved in the clearance of amyloid and that ApoE4 may be less able to provide a functional compensation compared to that of ApoE3. ApoE functions as a cholesterol acceptor in the brain and is also involved in cholesterol trafficking, a function dependent on the state of ApoE lipidation. Astrocytes and microglia are the primary sources of ApoE in the brain, with little ApoE being expressed by neurons. Here we are investigating astrocytes from ApoE knockout and wild-type mice to enable a comparison of (1) the secreted lipoproteins and (2) the release of pro-inflammatory cytokines. Differences are apparent in the protein composition of lipoprotein particles secreted in the absence of ApoE, and in the presence of different ApoE isoforms, compared to those produced by wild-type astrocytes. Furthermore, we anticipate that astrocytes from ApoE knockout mice will exhibit differential responses of cytokine release, compared to wild-type astrocytes, in response to stress. The results will elucidate mechanisms underlying the altered risk of developing AD that is caused by harbouring different ApoE alleles.
Where applicable, experiments conform with Society ethical requirements