Apolipoprotein E: a review of its roles in lipoprotein metabolism, neuronal growth and repair and as a risk factor for Alzheimer's disease

Apolipoprotein E: a review of its roles in lipoprotein metabolism, neuronal growth and repair and as a risk factor for Alzheimer's disease 1Apolipoprotein E (Apo E) is a polymorphic secretory glycoprotein expressed by a wide variety of tissues in mammals, particularly the liver and the brain (Mahley, 1988).Apo E recently attracted considerable attention when it was found that one of its alleles, apo E4, was associated with an increased risk for Alzheimer's disease (Strittmatter et al. 1993 a).This protein has been well studied with respect to its roles in lipoprotein metabolism in the peripheral circulation and in the nervous system.Accordingly, this protein's structure and function will be reviewed in order to place the potential roles of apo E in Alzheimer's disease into perspective. APO E PLAYS A CRITICAL ROLE IN LIPOPROTEIN METABOLISMLipids, including triglycerides, cholesterol and phospholipids, are relatively insoluble in aqueous medium.These substances must, therefore, be packed into lipoprotein particles for transport in the blood.Lipoproteins are spherical and have a common structural organization: a hydrophobic core consisting of cholesterol esters and triglycerides and a more hydrophilic shell consisting of phospholipids, unesterified cholesterol and apolipoproteins that are orientated with their hydrophilic domains towards the outside (reviewed by Havel & Kane, 1989).Lipids are transported in the blood by different lipoprotein pathways (Mahley, 1988), as follows.(1) Dietary lipids are packed into large lipoprotein particles, called chylomicrons, which are secreted into the lymph.These enter the circulation via the thoracic duct.The enzyme lipoprotein lipase, found in the vascular endothelium, hydrolyses triglycerides from the core of these particles to yield free fatty acids that are taken up primarily by adipocytes.The resultant denser, smaller, chylomicron remnants can be removed from the circulation by specific chylomicron remnant receptors on the liver cells.Apo E serves as the ligand on these particles that is recognized by the receptors.(2) Endogenously produced lipoproteins secreted by the liver are known as very low density lipoproteins (VLDL).These are also hydrolysed by lipoprotein lipase to yield smaller intermediate density lipoproteins (IDL).IDL can undergo two fates.First, they can be removed directly from the circulation by low density lipoprotein (LDL) receptors on liver cells.Again, apo E serves as the ligand for the recognition of IDL by these receptors.Alternatively, IDL can be further hydrolysed to yield even smaller and denser particles called low density lipoproteins (LDL).LDL are removed from the circulation by LDL receptors.Apo B-100, the sole apolipoprotein found on these particles, serves as the ligand for receptor-recognition in this case.(3) In a third pathway, a class of lipoproteins known as high density lipoproteins (HDL) absorb cholesterol from cholesterol-laden peripheral tissues, like the vascular endothelium.Some HDL contain apo E. These particles can be removed from the circulation by hepatic LDL receptors.The liver is a particularly important organ in cholesterol homeostasis as it is the major route for cholesterol excretion, which occurs in the bile.