Role of ApoE in conformation-prone diseases and atherosclerosis.
Three isoforms of human plasma apolipoprotein E (apoE) are ligands to lipoprotein receptors and influence in different manner the synthesis and catabolism of pro-atherogenic triglyceride-rich lipoproteins. Among three isoforms, the apoE4 isoform is associated with increased frequency of atherosclerosis and Alzheimer's disease (AD). The conformational transitions of beta-amyloid (Abeta) influenced by apoE and serum amyloid P (SAP) component are key events in AD development, the accumulation of intermediate diffusible and soluble oligomers of Abeta being of particular significance. SAP and apoE, in a different manner for the three isoforms, serve as "pathological" chaperones during the aggregation of Abeta considered as a conformation-prone process. In turn, apoE consisting of two domains self-associates in solution and intermediate structures differently populated for the three isoforms exist. The different structures of the three isoforms determine their different distribution among various plasma lipoproteins. The structural and metabolic consideration of the common apoE pathway(s) in two pathologies assumes four molecular targets for AD correction: (i) inhibition of the accumulation of diffusible soluble Abeta oligomers; (ii) inhibition of apoE synthesis and secretion by astrocytes, in particular, under lipid-lowering therapy; (iii) inhibition of the binding of apoE and/or SAP to Abeta; (iv) stimulation of the expression of cholesterol transporter ABCA1.
Dergunov
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AD
National Research Center for Preventive Medicine, Moscow, 101990, Russia. dergunov@img.ras.ru
D000544:Alzheimer Disease / Q000378:metabolism; D000686:Amyloidosis / Q000209:etiology* / Q000378:metabolism; D001057:Apolipoproteins E / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D011487:Protein Conformation; D020033:Protein Isoforms / Q000378:metabolism
D001057:Apolipoproteins E; D020033:Protein Isoforms