Glycation and Neurodegerative Diseases
Glycation is the non-enzymatic reaction of sugar with proteins, ribonucleic acids and fats. It occurs inside the body in the hyperglycemic state such as uncontrolled diabetes and impairs tissue function. It may occur locally or systemically in infections, that require high sugar, such as biofilms or in a high oxidative stress state. Externally, it occurs through cooking.
Most of glucose damage in glycation occurs indirectly through the reactive dicarbonyl intermediate, formed from an auto-oxidation reaction of sugar, and occurs independent of direct molecular sugar glycation reaction. The dicarbonyl so formed cross-links and damages substances and structures, in tissues, organs or organelles, such as insulin, the endoplasmic reticulum, mitochondria and the cell membrane--and causes stresses. Glycation affects all tissues. The more reactive advanced end products of glycoxidation or [indirectly] glycation(AGEs), which are more powerful electrophiles than the initial dicarbonyls themselves equally covalently cross-link proteins, ribonucleic acids and lipids and cause untold damage to tissue. The tissue becomes hard, less flexible, brittle and breaks rather easily, since most links are intra-unit, in, more or less, crystalline forms, with non-directional bonding, especially with the mineralization, where seeding is possible.
AGEs stimulate AGE receptors(RAGE)to activate endothelial cells and macrophages, leading to inflammation, with the production of cytokines; such as tumor necrotic factor(TNF) which in turn inhibits metalloproteinases and hence prevents the disposal of the plaque. They cause demyelination and cell membrane disruption as well as apoptosis. They also convert globular(unfolded) protein into cross-beta amyloid. Cross-beta glycated amyloid is a more powerful activator of RAGE and of glycogen synthetase kinase(GSK)than ordinary cross-beta amyloid, and hence a more toxic candidate for degenerative diseases. The current belief is that glycation is the principal culprit for amyloid formation in Alzheimer's and other neurodegenerative diseases. The products disrupt biological membranes, causing cellular, endoplasmic and oxidative stresses. The more insoluble form of glycated amyloid affects the cellular membrane, while the soluble form(about the size of membrane) penetrates the cytoplasmic membranes and attains the endoplasmic reticulum and mitochondrial membranes
Remedy to gylcation and glycoxidation will involve how we prepare our foods and what we eat. Overcooking, and at high temperatures, especially with simple sugars, will promote glycation. Sugar-grilling is especially harmful. Treating infections, such as Lyme disease, syphilis, which are in dire need of and use much sugar to produce their protective films, is essential, if we want to prevent degenerative diseases and slow down aging. Management of diabetes is a must. Stress management is essential.
Other scenarios that promote cross-linking are oxidative stress that promotes lipid peroxidation and inflammation, and inflammation proper; both of which produce malonyldialdehyde that forms cross-links in tissues and leads to advanced end products of lipid peroxidation(ALEs) and will cause similar tissue damage as AGEs, including demyelination. Just as with AGEs and gylycated amyloid, there are scavenger receptors for malonyldialdehyde and its cross-linked lipids such as low density lipoproteins(LDLP), as well as ALEs. But, very often, endocytosis gets overwhelmed, leading to severe inflammation
To promote the clearance of these toxins from the body, healthy inflammation with good functioning metalloproteinases--especially as proteases do not work very well extracellularly-- is required. Anti-oxidants will prevent glycoxidation and reduce cross-linking, and reduce the too high inflammation that encourages TNF, that in and of itself inhibits metalloproteasess. This may require steroid treatment that, through co-stimulation, tilts the balance from overstimulation over to low stimulation that gradates to a more useful form of cytokine production after recognition by the scavenger receptor and adaptations of the macrophage. These cross-linkers can then be cleared out of the body. Some elimination is through the formation of adducts with amino acids but these adducts must break for the final elimination(clearance)through the kidney to take place. For this to happen, a good kidney function is also necessary. Serrapeptase and nattokinase may prove useful to break up peptide bonds in the AGE and ALE adducts. NSAIDS and other antioxidants will prevent oxidation and hence reduce cross-linking. Naturally, aldehyde dehydrogenases in the body will reduce the reactive intermediates and prevent cross-linking.
Dr. Oliver Verbe Birnso MD
Most of glucose damage in glycation occurs indirectly through the reactive dicarbonyl intermediate, formed from an auto-oxidation reaction of sugar, and occurs independent of direct molecular sugar glycation reaction. The dicarbonyl so formed cross-links and damages substances and structures, in tissues, organs or organelles, such as insulin, the endoplasmic reticulum, mitochondria and the cell membrane--and causes stresses. Glycation affects all tissues. The more reactive advanced end products of glycoxidation or [indirectly] glycation(AGEs), which are more powerful electrophiles than the initial dicarbonyls themselves equally covalently cross-link proteins, ribonucleic acids and lipids and cause untold damage to tissue. The tissue becomes hard, less flexible, brittle and breaks rather easily, since most links are intra-unit, in, more or less, crystalline forms, with non-directional bonding, especially with the mineralization, where seeding is possible.
AGEs stimulate AGE receptors(RAGE)to activate endothelial cells and macrophages, leading to inflammation, with the production of cytokines; such as tumor necrotic factor(TNF) which in turn inhibits metalloproteinases and hence prevents the disposal of the plaque. They cause demyelination and cell membrane disruption as well as apoptosis. They also convert globular(unfolded) protein into cross-beta amyloid. Cross-beta glycated amyloid is a more powerful activator of RAGE and of glycogen synthetase kinase(GSK)than ordinary cross-beta amyloid, and hence a more toxic candidate for degenerative diseases. The current belief is that glycation is the principal culprit for amyloid formation in Alzheimer's and other neurodegenerative diseases. The products disrupt biological membranes, causing cellular, endoplasmic and oxidative stresses. The more insoluble form of glycated amyloid affects the cellular membrane, while the soluble form(about the size of membrane) penetrates the cytoplasmic membranes and attains the endoplasmic reticulum and mitochondrial membranes
Remedy to gylcation and glycoxidation will involve how we prepare our foods and what we eat. Overcooking, and at high temperatures, especially with simple sugars, will promote glycation. Sugar-grilling is especially harmful. Treating infections, such as Lyme disease, syphilis, which are in dire need of and use much sugar to produce their protective films, is essential, if we want to prevent degenerative diseases and slow down aging. Management of diabetes is a must. Stress management is essential.
Other scenarios that promote cross-linking are oxidative stress that promotes lipid peroxidation and inflammation, and inflammation proper; both of which produce malonyldialdehyde that forms cross-links in tissues and leads to advanced end products of lipid peroxidation(ALEs) and will cause similar tissue damage as AGEs, including demyelination. Just as with AGEs and gylycated amyloid, there are scavenger receptors for malonyldialdehyde and its cross-linked lipids such as low density lipoproteins(LDLP), as well as ALEs. But, very often, endocytosis gets overwhelmed, leading to severe inflammation
To promote the clearance of these toxins from the body, healthy inflammation with good functioning metalloproteinases--especially as proteases do not work very well extracellularly-- is required. Anti-oxidants will prevent glycoxidation and reduce cross-linking, and reduce the too high inflammation that encourages TNF, that in and of itself inhibits metalloproteasess. This may require steroid treatment that, through co-stimulation, tilts the balance from overstimulation over to low stimulation that gradates to a more useful form of cytokine production after recognition by the scavenger receptor and adaptations of the macrophage. These cross-linkers can then be cleared out of the body. Some elimination is through the formation of adducts with amino acids but these adducts must break for the final elimination(clearance)through the kidney to take place. For this to happen, a good kidney function is also necessary. Serrapeptase and nattokinase may prove useful to break up peptide bonds in the AGE and ALE adducts. NSAIDS and other antioxidants will prevent oxidation and hence reduce cross-linking. Naturally, aldehyde dehydrogenases in the body will reduce the reactive intermediates and prevent cross-linking.
Dr. Oliver Verbe Birnso MD
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