Sandbox Reserved 595: Difference between revisions
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=Background= | =Background= | ||
Apolipoprotein E is a member of the apolipoprotein family (NMR structure [[217b]]). This soluble protein is produced primarily in the liver and brain; and it is located principally in the plasma and in the central nervous system (CNS)'<ref>Han X. 2010. T he pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41(2-3): 97-106.</ref>'. The systemic transport of cholesterol and other lipids is this protein's main role in the body '<ref>OMIM.Omim.org/entry/107741.</ref>'. One minor function it may exhibit is that of immune regulation '<ref>OMIM.Omim.org/entry/107741.</ref>'. ApoE may also play a role in synaptic integrity and plasticity ( | Apolipoprotein E is a member of the apolipoprotein family (NMR structure [[217b]]). This soluble protein is produced primarily in the liver and brain; and it is located principally in the plasma and in the central nervous system (CNS)'<ref>Han X. 2010. T he pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41(2-3): 97-106.</ref>'. The systemic transport of cholesterol and other lipids is this protein's main role in the body '<ref>OMIM.Omim.org/entry/107741.</ref>'. One minor function it may exhibit is that of immune regulation '<ref>OMIM.Omim.org/entry/107741.</ref>'. ApoE may also play a role in synaptic integrity and plasticity '<ref>Arold, S. et al. 2012. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol 123(1):39-52.</ref>'. Particular isoforms, ε2 and ε4 are implicated in hyperlipoproteinemia (HLP III) and late onset Alzheimer's disease (LOAD). | ||
=Genetics= | =Genetics= | ||
The ApoE gene stores the information responsible for the protein apolipoprotein E. ApoE's cytogenic location is on the long q arm of chromosome 19, in the 13.2 position (19q13.2). It stretches from base pair 45,409,038 to bp 45,412,649 (X). Polymorphisms for this gene include three main alleles, epsilon 2, epsilon 3, and epsilon 4 '<ref>OMIM.Omim.org/entry/107741.</ref>'. The ε3 allele is the most frequent in all human groups. ε4 has a higher frequency in populations such as Pygmies and Khoisan, Aboriginies of Malaysia and Australia, Papuas, some Native Americans, and Lapps. The frequency of ε2 fluctuates without an apparent trend; but, it is abscent in Native American populations '<ref>OMIM.Omim.org/entry/107741.</ref>'. | The ApoE gene stores the information responsible for the protein apolipoprotein E. ApoE's cytogenic location is on the long q arm of chromosome 19, in the 13.2 position (19q13.2). It stretches from base pair 45,409,038 to bp 45,412,649 (X). Polymorphisms for this gene include three main alleles, epsilon 2, epsilon 3, and epsilon 4 '<ref>OMIM.Omim.org/entry/107741.</ref>'. The ε3 allele is the most frequent in all human groups. ε4 has a higher frequency in populations such as Pygmies and Khoisan, Aboriginies of Malaysia and Australia, Papuas, some Native Americans, and Lapps. The frequency of ε2 fluctuates without an apparent trend; but, it is abscent in Native American populations '<ref>OMIM.Omim.org/entry/107741.</ref>'. | ||
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The protein, apolipoprotein E, has an important role in lipid metabolism; principally, it serves as a carrier protein. ApoE combines with lipids in the body to form lipoprotein particles (X,Z). These lipoprotein particles have hydrophobic lipids situated at the core and hydrophilic side chains made of amino acids (Z). Specifically, apoE is responsible for packaging cholesterol,other lipids, and fat soluble vitamins and transporting them systemically '<ref>Han X. 2010. T he pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41(2-3): 97-106.</ref>'(X). | The protein, apolipoprotein E, has an important role in lipid metabolism; principally, it serves as a carrier protein. ApoE combines with lipids in the body to form lipoprotein particles (X,Z). These lipoprotein particles have hydrophobic lipids situated at the core and hydrophilic side chains made of amino acids (Z). Specifically, apoE is responsible for packaging cholesterol,other lipids, and fat soluble vitamins and transporting them systemically '<ref>Han X. 2010. T he pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41(2-3): 97-106.</ref>'(X). | ||
Synthesis of this protein primarily occurs in the liver; approximately three-fourths of plasma apoE is generated in the liver by hepatic parenchymal cells (X). In this location, apoE is included as a major component of very-low density lipoproteins (VLDL) (X,Z). VLDL serves to remove excess cholesterol from the blood and to carry it to the liver for processing. Thus, apoE acts as a cholesterol chaperone ( | Synthesis of this protein primarily occurs in the liver; approximately three-fourths of plasma apoE is generated in the liver by hepatic parenchymal cells (X). In this location, apoE is included as a major component of very-low density lipoproteins (VLDL) (X,Z). VLDL serves to remove excess cholesterol from the blood and to carry it to the liver for processing. Thus, apoE acts as a cholesterol chaperone '<ref>Arold, S. et al. 2012. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol 123(1):39-52.</ref>'. Maintaining optimal levels of cholesterol is crucial for the prevention of disorders that affect the heart and blood levels (X). Triglycerides are also transported to the liver tissue with the aid of VLDL (Z). ApoE is essential for the normal catabalism of triglyceride-rich lipoprotein constituents '<ref>Arold, S. et al. 2012. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol 123(1):39-52.</ref>'. In the plasma, apoE will associate with most lipoproteins, however, n the central nervous system, it mainly associates with high-density lipoproteins (HDL) '<ref>Han X. 2010. T he pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41(2-3): 97-106.</ref>'. | ||
Another way in which apoE is involved in the metabolsim of lipids is through binding to the low denstiy lipoprotein receptor; apoE assists in both the transportation of lipids and the facilitation of their uptake. ApoE mediates the receptor binding of apoE lipoprotein particles to the LDL recptor, an action that initiates the cellular uptake of lipoproteins (Z). Following the receptor-mediated endocytosis of apoE-containing lipoprotein particles by LDL receptor family member, apoE may undero one of two fates. ApoE can either be degraded, or it can be recycled back to the cell surface '<ref>Han X. 2010. T he pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41(2-3): 97-106.</ref>'. One other function that apoE plays with regards to lipid metabolism takes place within the intestinal tract. ApoE has the ability to incorporate into intestinally synthesized chylomicrons. By doing so, apoE can transport dietary triglycerides and cholesterol (Z). | Another way in which apoE is involved in the metabolsim of lipids is through binding to the low denstiy lipoprotein receptor; apoE assists in both the transportation of lipids and the facilitation of their uptake. ApoE mediates the receptor binding of apoE lipoprotein particles to the LDL recptor, an action that initiates the cellular uptake of lipoproteins (Z). Following the receptor-mediated endocytosis of apoE-containing lipoprotein particles by LDL receptor family member, apoE may undero one of two fates. ApoE can either be degraded, or it can be recycled back to the cell surface '<ref>Han X. 2010. T he pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41(2-3): 97-106.</ref>'. One other function that apoE plays with regards to lipid metabolism takes place within the intestinal tract. ApoE has the ability to incorporate into intestinally synthesized chylomicrons. By doing so, apoE can transport dietary triglycerides and cholesterol (Z). | ||
==Neurological== | ==Neurological== | ||
In the brain, apoE is primarily produced by astrocytes. ApoE in the brain is thought to deliver cholesterol and other lipids to neurons through the process of receptor-mediated endocytosis (R). It may also play in important role in synaptic integrity and plasticity ( | In the brain, apoE is primarily produced by astrocytes. ApoE in the brain is thought to deliver cholesterol and other lipids to neurons through the process of receptor-mediated endocytosis (R). It may also play in important role in synaptic integrity and plasticity '<ref>Arold, S. et al. 2012. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol 123(1):39-52.</ref>'. For, cholesterol released from apoE-containing lipoprotein particles is used to support synaptogenesis as well as the maintenance of synaptic connections '<ref>Han X. 2010. T he pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease. Mol Neurobiol 41(2-3): 97-106.</ref>'. | ||
==Immunological== | ==Immunological== | ||
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=Clinical Relevance= | =Clinical Relevance= | ||
==Late Onset Alzheimer's Disease== | ==Late Onset Alzheimer's Disease== | ||
Late onset Alzheimer's disease is characterized by the presence of plaques. [[Amyloid beta]], a hydrophobic peptide, is a major component of these plaques (T). ApoE has been observed to tightly bind with Aβ, an interaction that is hypothesized to influence the deposition of Aβ, thus contributing to the pathogenesis of LOAD (F). A significant amount of Aβ is concentrated within the small paopulation of apoE-containing synapses; these two molecules have been observed to be highly colocalized in these synapses ( | Late onset Alzheimer's disease is characterized by the presence of plaques. [[Amyloid beta]], a hydrophobic peptide, is a major component of these plaques (T). ApoE has been observed to tightly bind with Aβ, an interaction that is hypothesized to influence the deposition of Aβ, thus contributing to the pathogenesis of LOAD (F). A significant amount of Aβ is concentrated within the small paopulation of apoE-containing synapses; these two molecules have been observed to be highly colocalized in these synapses '<ref>Arold, S. et al. 2012. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol 123(1):39-52.</ref>'. Concentrations of amyloid-β in the extracellular space of the brain are indicative of the balance between the synthesis and clearance of Aβ (S). In fact, the Aβ concentration per synaptic terminal is notably lower in control subjects as compared to those exhibiting AD '<ref>Arold, S. et al. 2012. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol 123(1):39-52.</ref>'. A deficit in clearance, rather than aberrant synthesis, is thought to be a factor in plaque formation '<ref>Arold, S. et al. 2012. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex. Acta Neuropathol 123(1):39-52.</ref>'. ApoE4's ability to bind to Aβ is impaired, subsequently resulting in a reduced amount of receptor-mediated uptake and cellular metabolism of the apoE/Aβ complex. Therefore, the E4 isoform of apoE is responsible for the reduced Aβ clearance that is characteristic of brains affected by AD (F). | ||
Inheritance of the ε4 allele is considered to be the strongest genetic risk factor for late onset Alzheimer's disease (LOAD) (A,M,N, O). Homozygosity for ε4 is associated with senile plaques that are more developed (O). Isoform-dependent differences in Aβ plaque deposition exist, with apoE4 having the highest association and E2 displaying a seemingly protective role against LOAD (N,S). ApoE4 and its C-terminal truncated fragments have been located in plaques and neurofibrillary tangles within the brain in patients with LOAD (O). Upon interaction with Aβ, apoE4 becomes a partially unfolded intermediary; this transformation occurs due to the frustration of the network of salt bridges. The 4-helix bundle opens, the hydrophobic core becomes exposed, and the protein is rendered incapable of clearing Aβ (T). | Inheritance of the ε4 allele is considered to be the strongest genetic risk factor for late onset Alzheimer's disease (LOAD) (A,M,N, O). Homozygosity for ε4 is associated with senile plaques that are more developed (O). Isoform-dependent differences in Aβ plaque deposition exist, with apoE4 having the highest association and E2 displaying a seemingly protective role against LOAD (N,S). ApoE4 and its C-terminal truncated fragments have been located in plaques and neurofibrillary tangles within the brain in patients with LOAD (O). Upon interaction with Aβ, apoE4 becomes a partially unfolded intermediary; this transformation occurs due to the frustration of the network of salt bridges. The 4-helix bundle opens, the hydrophobic core becomes exposed, and the protein is rendered incapable of clearing Aβ (T). | ||