Lipoprotein Abnormalities Associated with Alzheimer Disease, Diabetes, Atherosclorosis - Essay Example

? Lipoprotein abnormalities associated with Alzheimer’s disease, Diabetes, and Atherosclerosis Lipoprotein abnormalities associated with Alzheimer’s disease, Diabetes, and Atherosclerosis The plasma lipoproteins are water soluble macromolecules that represent complexes of lipids, and one or more specific proteins referred to as apolipoproteins. Lipoproteins are separated into various categories on the basis of density at which they float through ultracentrifugation. These macromolecules are further categorized depending on electrophoretic ability, particle size or affinity chromatography. These specific classes have distinct metabolic functions. The human plasma lipoproteins are commonly classified into six major classes. Chylomicrons form the largest proteins approximately >100nm in diameter. They are synthesized within the intestines and transport dietary triglyceride and cholesterol from absorption sites to various cells of the body. The triglycerides of these particles are hydrolyzed within the plasma compartment through catalysis by lipoprotein lipase. Fatty acids generated through the breakdown are used as a source of energy by the various cells or are taken up by adipocytes (Zhang, Song, Cavigiolio, Ishida, Zhang, Kane, Weisgraber, Oda, Rye, Pownall & Ren, 2011). Lipoprotein particles generated through the action of lipoprotein lipase on Chylomicrons are called chylomicron remnants. The other category of lipoproteins is the very low density lipoproteins (VLDL, with a density of less than 1.006g/ml and a diameter ranging between 30-90nm. These particles transport triglycerides and cholesterol from the liver for re-distribution to other tissues in the body. In the plasma compartment, the triglycerides of the VLDL undergo hydrolysis through lipoprotein lipase. This reaction results into the generation of smaller, cholesterol-enriched lipoproteins including intermediate density lipoproteins (IDL). Intermediate density lipoproteins have a density of between 1.006 -1.019g/ml. the other particles generated from the hydrolysis of VLDL are the low density lipoproteins (LDL) which have a density of between 1.019-1.063 g/ml. Low density lipoproteins represent the end product of VLDL catabolism, and are the main cholesterol transporting lipoproteins in the plasma (Zhang, Song, Cavigiolio, Ishida, Zhang, Kane, Weisgraber, Oda, Rye, Pownall & Ren, 2011). High density lipoproteins (HDL) have a density of between 1.063-1.21g/ml, and appear to arise from numerous sources including the intestine and liver. These particles are the smallest of all the lipoproteins which are involved in a process called reverse cholesterol transport. This is a hypothesized pathway whereby HDL acquires cholesterol from peripheral tissues and transports the cholesterol directly or indirectly to the liver (Mahley, Innerarity, Rall & Weisgraber, 2008). The apolipoprotein components of the major plasma lipoproteins can be visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Apolipoproteins of the numerous lipoproteins modulate the metabolism of lipoproteins and determine the unique roles of these lipoproteins in lipid metabolism. A well established function of the apolipoprotein is their involvement in the transport and re-distribution of lipids within several tissues (Mahley, Innerarity, Rall & Weisgraber, 2008). The delivery of lipids to specific to specific cells and tissues involves the recognition of specific apolipoproteins by cell surface lipoprotein receptors. Another function of apolipoproteins involves their role as cofactors for enzymes of lipid metabolism. Another function for specific apolipoproteins involves their role in the maintenance of the structure of lipoproteins. Numerous apolipoproteins including apoB, apoA-I and apoE appear to stabilize the micellar structure of the lipoproteins. In addition, these apolipoproteins together with phospholipids on the surfaces of the particles provide a hydrophilic surface. Apolipoprotein E is a component of the chylomicrons, VLDL, chylomicron remnants and HDL with apoE. The plasma concentration of apoE ranges between 3-7mg/dl among people with normolipidemia (Mahley, Innerarity, Rall & Weisgraber, 2008). It can however elevate to between 20-60mg/dl in individuals with certain types of hyperlipidemia. Apolipoprotein E displays a sophisticated isoform pattern due to the presence of multiple, genetically determined alleles at a single locus. Moreover, the isoform nature of the apoE is due to the presence of pos-translational sialylation. Six common phenotypes of apoE have been elucidated through isoelectric focusing. These include three homozygous isoforms namely E4/4, E3/3 and E2/2 while the three heterozygous isoforms include E4/3, E4/2 and E3/2. The major isoforms of apolipoprotein E have pI values ranging from 5.7 to 6.2 (Mahley, Innerarity, Rall & Weisgraber, 2008). On the other hand, the minor isoforms of apoE represent the glycosylated forms of the major protein. The most common phenotype of apoE among humans is the E3/3. Analyses of the amino acid sequences have revealed that apoE is a polypeptide composed of 299 amino acids, with a molecular weight of 34,200. Apolipoprotein E is one of the commonly studied and appears to have several functions. The apoE is involved in transport and metabolism of cholesterol, receptor-mediated uptake of specific lipoproteins and heparin binding. ApoE also functions in the formation of cholesteryl ester-rich particles, lipolytic processing of type III ?-VLDL. This apolipoprotein has also been shown to inhibit mitogenic stimulation of lymphocytes (Mahley, Innerarity, Rall & Weisgraber, 2008). Alzheimer’s disease (AD) is a destructive neurodegenerative disorder that affects approximately 4 million people in America. AD is a clinical pathological disease that has numerous causes. The predominant autosomal AD is relatively rare, accounting for less than 5% of the patients with AD. Autosomal predominant AD arises due to mutations in one of the three different genes namely amyloid precursor protein, presenilin 1 or presenilin 2. However, the most common form of Alzheimer’s disease is not the inherited dominant autosomal type but the sporadic. A number of risk factors for sporadic AD have been identified including advancing age and previous trauma. Moreover, the inheritance of certain alleles of the apolipoprotein E gene has been identified as a causative agent. AD s characterized by a slow progressive loss of cognition, behavioral changes and loss of independence. This consequently leads to complete destruction of the personality (Cedazo-Minguez, 2009). The common pathogenic event that occurs in all types of AD is the abnormal accumulation of the A? in amyloid deposits and cerebral blood vessels. ApoE is one of the main apolipoproteins within the plasma and the principal cholesterol carrier protein in the brain (Puglielli, Tanzi & Kovacs, 2008). The connection between AD and ApoE ?4 remains a largely undefined at the mechanistic level. ApoE represents the most important genetic risk factor for sporadic AD. Humans differ from most other mammals in having three different common alleles of apoE: ?2, ?3 and ?4. The inheritance of apoE4 is linked with a dose-dependent increased risk and younger age of onset of sporadic AD. Most patients with sporadic AD carry at least a single copy of apoE4. Nonetheless, it is imperative to note that not every individual who inherits a copy of apoE4 will develop AD, and many AD patients lack apoE4. On the contrary apoE4, the inheritance of apoE2 reduces the risk and delays the age of onset of AD. This suggests a possible protective effect from inheritance of this allele. ApoE2, ApoE3 and ApoE4 code for three distinct isoforms namely apoE2, apoE3 and apoE4 respectively (Bassett, Montine, Neely, Swift & Montine, T., 2007). Inheritance of the ?4 allele of the apolipoprotein E gene increases the risk for familial and sporadic onset of Alzheimer’s disease (AD) compared to two common alleles namely ? 2 and ?3. The link of apolipoprotein E E4 allele with elevated serum total cholesterol (TC), low density lipoprotein (LDL) cholesterol and apolipoprotein B and with an increased risk of AD raises the question whether there is a relation between serum lipoprotein concentrations, apolipoprotein E polymorphism and AD risk. A number of studies have found that there are elevated concentrations of serum TC, LDL cholesterol and apolipoprotein and apolipoprotein B in AD patients (Solfrizzi, D’Introno, Colaccio, Capurso, Basile & Carpuso, A., 2008). Studies in transgenic mouse model expressing human APP (PDAPP) suggest that apoE contributes to the deposition of A?. Deposition of A? linked with severe neuritic dystrophy has been shown to be more pronounced in the ApoE ?4 isoform. ApoE may also mediate internalization of A? through its binding to the LDL receptor-related protein. The internalization of A? is not necessarily followed by its degradation. Instead, A? aggregates within the endolytic compartment and can be released again in the fibrillary in a more toxic form. In addition to the direct facilitation of A? internalization and aggregation, apoE4 may modulate the homeostasis of brain cholesterol. It is able to accomplish this by modifying lipoprotein-particle formation. Within the plasma, apoE4 tends to associate with VLDL particles, which contain higher cholesterol content. On the other hand, apoE3 prefers to connect to HDL (Puglielli, Tanzi & Kovacs, 2009). Individuals homozygous for the apoE ?4 allele a higher levels of cholesterol in plasma and 24S-hydroxycholesterol in the cerebrospinal fluid. 24S-hydroxycholesterol is a catabolic derivative of cholesterol and forms the main metabolic route for cholesterol clearance from the brain (Lane & Farlow, 2008). The lipoproteins produced in the brain are very unique in various aspects including density, position and other properties. Cerebrospinal fluid (CSF) lipoproteins have a density of less than 1.210 g/ml. Therefore, it is postulated that the different isoforms of apoE modify brain cholesterol homeostasis by preferentially associating with specific lipoprotein particles. Consequently, the role of apoE in maintaining cholesterol balance within the brain may contribute to an increase in risk for AD associated with apoE ?4 (Puglielli, Tanzi & Kovacs, 2009). AD can be determined by the analysis of CSF lipoproteins incubated with Neuro2A cell at physiologic concentrations to examine the neurotoxicity. These cells have been extensively used to study the neurotrophic effects of human apoE-containing lipid particles. These cells are also capable of binding and internalizing artificial lipid particles bearing human apoE isoforms. Neurotoxicity is then determined by Live/Dead Assay against the Neuro2A cells with incorporation of controls (Bassett, Montine, Neely, Swift & Montine, 2005). Type 2 diabetes is linked to a cluster of interrelated plasma abnormalities, including decreased HDL cholesterol, predominance of small dense LDL particles and increased triglycerides. These anomalies are also a characteristic trait of the insulin resistance syndrome or metabolic syndrome. In fact, pre-diabetic patients often show an atherogenic pattern of risk factors exemplified by elevated levels of total cholesterol. Other features among these individuals include elevated cholesterol, LDL and triglycerides with reduced levels of HDL cholesterol (Pascot, Lemieux, Prud’homme, Tremblay, Nadeau, Couillard, Despre's, 2008). Insulin resistance has pronounced effects on the lipoprotein size and subclass particle concentrations for HDL, LDL and VLDL (Krauss, 2008). The alteration in metabolism of triglyceride-rich lipoproteins is critical in the pathophysiology of the atherogenic dyslipidemia of diabetes. Lipoprotein a, an LDL-like particle with apolipoprotein a bound to apolipoprotein B100 through a disulphide bond is believed to have atherogenic property (Solfrizzi, D’Introno, Colaccio, Capurso, Basile & Carpuso, 2008). The most common alteration of lipoproteins in diabetes is an increase in VLDL, as typified by elevated total triglyceride or VLDL triglyceride concentrations. It has been postulated that diabetic subjects with total triglyceride concentrations higher than 300 or 400 mg/dl are those who have genetic defects in the metabolism of lipoprotein. In addition to stimulating an overproduction of VLDL triglyceride, non-insulin dependent diabetes appears to be linked to a defect in clearance of VLDL triglyceride. Reduced fractional catabolic rates (FCR) have been reported in VLDL triglyceride metabolism (Krauss, 2007). Results obtained from studies on VLDL apolipoprotein B metabolism among diabetes subjects indicate that there is a clearance defect similar to that for VLDL triglyceride. However, VLDL apoB production may be influenced primarily by obesity. Individuals with diabetes have a reduction in fractional catabolic rate for VLDL apoB. Moreover, a greater proportion of the VLDL apoB in diabetes subjects is metabolized without conversion to LDL (Wilensky, R., & Macphee, C. (2009). Among diabetic patients, there are increased concentrations of LDL-cholesterol (LDL-C), which can be more pathogenic. Partly, this may be due to the presence of small, dense LDL-c particles and oxidation of glycated LDL-C particles. The lipid profile among diabetic patients is commonly characterized by hypertriglyceridemia and decreased HDL cholesterol concentrations. Essentially, LDL-C and total cholesterol concentrations in type 2 diabetes are not significantly different from non-diabetic concentrations. However, the difference may have enhanced atherogenicity (Krentz, 2008). The homeostasis of lipids and innate immune responses are connected, with the metabolism of lipoprotein and macrophages sharing several host defense mechanisms and signaling pathways. For instance, as earlier noted in the introduction, lipoproteins play an important role in host defense. However, in the development of atherosclerosis, an altered form of vascular inflammation, monocytes-derived macrophages are recruited in large quantities to locations of oxidized lipoprotein accumulation within the arterial wall. Moreover, macrophage scavenger receptors that recognize and mediate uptake of oxidatively modified lipoproteins are also implicated in innate recognition of apoptotic cells or pathogens. Lipoprotein-associated phospholipase A2 (Lp-PL A2) is an enzyme that is ideally suited to overlap both processes. Also referred to as the platelet-activating factor acetyl-hydrolase (PAF-AH) or PL A2 type VIIA, Lp-PL A2 is actively released by monocytes-derived macrophages. The enzyme is also secreted by mast cells and T-lymphocytes, and is primarily linked with LDL in human plasma (Wilensky & Macphee, 2009). Lipoprotein a (Lp a) is composed of a low-density lipoprotein (LDL)-like particle to which a large, highly glycosylated apolipoprotein A (Apo A) is connected by a single disulphide bridge. Plasma Lp A levels vary widely between individuals and are largely determined by their Apo A size, to which they are inversely related. Apolipoprotein A is highly polymorphic due to a variable number of tandemly repeated copies of a motif resembling kringle IV of plasminogen. The physiological role of lipoprotein A is largely unknown. However, lipoprotein A is a recognized independent risk factor for atherosclerotic cardiovascular disease with unknown mechanisms. In normolipidemic human plasma with no detectable Lp (a) levels, Lp-PL A2 is mainly linked with LDL, whereas a small proportion of enzyme activity is associated with HDL Wilensky, R., & Macphee, C. (2009). Lp (a) is an atherogenic lipoprotein present in atherosclerotic conditions but not in normal vessel walls. In the early plaque, most of the Lp (a) is located within endothelial cells where it significantly influences function of the cell. In developed lesions, Lp (a) is found dominantly in the intima, where it is primarily co-localized with foam cells. Lp (a) contributes to the formation of foam cells because it readily undergoes oxidation and aggregation. It can also be subjected to phospholipase A2 modification, in which case it can be taken up by scavenger receptors of macrophages (Tsimakas, Tsironis & Tselepis, 2009). The oxidation of LDL results in a range of alterations affecting phospholipids and apolipoprotein B (apoB) constituents that render this molecule unique from its native form. These reactions include formation of lipid hydroperoxides and aldehydes such as malondialdehyde and 4-hydroxynonenal. These resulting constituents react with lysine residues of apoB, altering the physicochemical properties of LDL. Increased levels of circulating oxidized LDL are associated with morphological proof of plaque vulnerability, endothelial dysfunction and are elevated in patients with acute coronary syndromes (Zalewski & Macphee, 2008). Current research focusing on understanding atherosclerosis as well as the growing analytical abilities have led to the discovery of associations between several soluble biomarkers and cardiovascular risk. In some instances, the upstream events result in the up-regulation of the analyte such as the C-reactive protein and serum amyloid A. On the contrary, other biomarkers are thought to be directly implicated in disease development. An example of such a biomarker is the myeloperoxidase. At the moment, serum levels of malondialdehyde, a marker of lipid oxidation, are also strongly predictive of atherosclerosis. This assay may reflect a greater exposure the vessel wall to oxidatively altered LDL, but it also indicates an elevation in the substrate for Lp-PLA2 (Zalewski & Macphee, 2008). References Bassett, C., Montine, K., Neely, D., Swift, L., & Montine, T. (2007). Cerebrospinal Fluid Lipoproteins in Alzheimer’s Disease. Microscopy Research and Technique, 282–286. Cedazo-Minguez, A. (2009). Apolipoprotein E and Alzheimer’s disease: molecular mechanisms and therapeutic opportunities. J. Cell. Mol. Med, 1227-1238. Howard, B. (2007). Lipoprotein metabolism in diabetes mellitus. Journal of Lipid Research, 613-628. Jellinger, P., Mehta, A., Handelsman, Y., & Shepherd, M. (2012). American Association of Clinical Endocrinologist' Guidelines for the Management of Dyslipidemia and Prevention of Atherosclerosis. Endocrine Practice, 1-78. Krauss, R. (2007). Lipids and Lipoproteins in Patients With Type 2 Diabetes. Diabetes Care, 1496–1504. Krentz, A. (2008). 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