Amyloidosis, advanced glycation end products and Alzheimer disease.
Explore the source record for details and available documents.
Alzheimer Disease↗
Biomedical subjects
V M Monnier
Publications and source records attributed to V M Monnier.
Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction.
The role of glyoxal and glycolaldehyde in protein cross-linking and N epsilon-(carboxymethyl)lysine (CML) formation during Maillard reaction under physiological conditions was investigated. Incubation of bovine serum albumin with these reagents lead to rapid formation of C-2-imine cross-links and CML. Initial CML formation rate from glyoxal was not dependent on oxidation, suggesting an intramolecular Cannizzaro reaction. CML formation from glucose/lysine or Amadori product of both was strongly dependent on oxidation. Blocking of Amadori product by boric acid totally suppressed CML formation from Amadori product, but only by 37% in the glucose/lysine system. Trapping of glyoxal with aminoguanidine hardly suppressed CML formation from Amadori product, whereas it blocked 50% of CML production in the glucose/lysine system. While these results would support a significant role for glucose autoxidation in CML formation, the addition of lysine to a glucose/aminoguanidine incubation system catalyzed glyoxal-triazine formation 7-fold, thereby strongly suggesting that glucose autoxidation is not a factor for glyoxal-mediated CML formation. Based on these results, it can be estimated that approximately 50% of the CML forming in a glucose/lysine system originates from oxidation of Amadori product, and 40-50% originates from a pre-Amadori stage largely independent from glucose autoxidation. This step may be related to the so-called Namiki pathway of the Maillard reaction.
Acetaldehyde↗
Early AGEing and Alzheimer's.
Explore the source record for details and available documents.
Alzheimer Disease↗
Chromatographic evidence for pyrraline formation during protein glycation in vitro and in vivo.
Pyrraline (epsilon-2-(formyl-5-hydroxymethyl-pyrrol-1-yl)-L-norleucine) is an advanced Maillard reaction product formed from 3-deoxyglucosone in the non-enzymatic reaction between glucose and the epsilon-amino group of lysine residues on proteins. Although its presence in vivo as well as in in vitro incubations of proteins with sugars has been documented by immunochemical methods using polyclonal and monoclonal antibodies, its formation in proteins has recently been questioned by similar methodology. To clarify this issue, we investigated pyrraline formation in proteins following alkaline hydrolysis and quantitation by high-performance liquid chromatography on a C18 reverse-phase column. Time- and sugar concentration-dependent increase in pyrraline formation was noted in serum albumin incubated with either 100 mM glucose or 50 mM 3-deoxyglucosone. Formation of pyrraline from 3-deoxyglucosone was rapid at slightly acidic pH, confirming its synthetic pathway through this Maillard reaction intermediate. Low levels of pyrraline (< 10 pmol/mg protein) were also detected in a pool of human skin collagen by this method, but no age effect was apparent. Using a slightly different approach, pyrraline-like material was detected in human plasma proteins following enzyme digestion and analysis by high performance liquid chromatography. Plasma from diabetic patients showed a significant increase in pyrraline-like material compared to controls. The levels in diabetic and normal individuals were 21.6 +/- 9.56 and 12.8 +/- 5.6 pmol per mg protein, respectively (P = 0.005), reflecting thereby the elevated levels of the immediate precursor of pyrraline, 3-deoxyglucosone, in diabetic plasma.
Animals↗
Novel degradation pathway of glycated amino acids into free fructosamine by a Pseudomonas sp. soil strain extract.
A Pseudomonas sp. soil strain, selected for its ability to grow on epsilon-(1-deoxyfructosyl) aminocaproic acid, was induced to express a membrane-bound enzymatic activity which oxidatively degrades Amadori products into free fructosamine. Apparent Km values for fructosyl aminocaproate, epsilon-fructosyl lysine, fructosyl glycine, and ribated lysine were 0.21 mM, 2.73 mM, 3.52 mM, and 1.57 mM, respectively. The enzyme was also active against alpha-fructosyl lysine and borohydride-reduced Amadori product, weakly active with ribated and glycated polylysine, and inactive with reducing sugars, amino acids, and glycated proteins. The enzymatic activity was highest at pH 6.5 and 25 degrees C in 0.1 M sodium phosphate, while over 80% of the activity was lost above 65 degrees C. Complete inhibition was observed by HgCl2, NaN3, and NaCN suggesting a role for SH groups and copper in the enzymatic activity. The reaction products were characterized by 1H NMR, 13C NMR, and GC/MS and found to correspond to 1-deoxy-1-aminofructose, i.e. free "fructosamine," and adipic acid. Confirmation of the free fructosamine structure was based on the complete spectroscopic identity of the borohydride reduction product with commercially available glucamine (1-amino-1-deoxyglucitol). The new enzyme is provisorily classified as fructosyl N-alkyl amino acid oxidase (EC 1.5.3) (fructosyl-amino acid:oxygen oxidoreductase) and may thus belong to a novel class of "Amadoriases" which deglycate Amadori products oxidatively. In contrast, however, the new enzyme acts on the alkylamine bond rather than the ketoamine bond of the Amadori product.
Amino Acids↗
Age-related increase in an advanced glycation end product in penile tissue.
Nonenzymatic glycosylation (glycation) of proteins, often referred to as the Maillard reaction, has been proposed to play a role in age and diabetes-related processes by forming protein and DNA adducts and cross-links. These cross-links may contribute to erectile dysfunction by scavenging nitric oxide, which is needed for erection. As the basis for a possible role of the advanced Maillard reaction in age-related erectile dysfunction, we investigated the presence of the specific advanced glycation endproduct (AGE) pentosidine in penile corpus cavernosum tissue and penile tunica albuginea tissue as a function of age. A total of 23 penile tissue specimens were obtained at autopsy, from which 19 samples of tunica albuginea and 21 samples of corpus cavernosum were derived. In addition, 13 penile corporal and tunical specimens were procured at the time of insertion of a penile prosthesis, from which 12 tunica albugineal specimens and 10 samples of corpus cavernosum were derived. Collagen was extracted with acetic acid and pepsin digestion, and the final insoluble collagen product was acid-hydrolyzed with 6 N HCL for 24 h at 110 degrees C. Pentosidine was quantified by high-performance liquid chromatography using a reverse-phase column. The level of pentosidine (expressed in picomoles per milligram of insoluble collagen) was found to increase with age in cadaver as well as living penile corporal and tunical albugineal tissues. Best-fit analysis revealed an exponential increase in both types of cadaver penile tissue, with regression equations of y = 15.29 x 10(9.9e-3x), R2 = 0.79, being obtained in the tunica and y = 13.2 x 10(7.63e-3x), R2 = 0.56, in the corpora. These correspond to 6- and 4-fold increases in pentosidine levels from puberty to the age of 100 years (P < 0.05), respectively. Mean pentosidine levels were higher in the tunica than in the corpora. Comparison of pentosidine levels in the tunica versus the corpora revealed a weakly linear correlation (y = 24.88 + 1.08x, R2 = 0.32). Levels in the tunical and corporal specimens from the living human specimens fell with the predicted confidence intervals of the cadaveric tissue. Tunical specimens from patients who underwent repair or revision of a previously inserted penile prosthesis had very low levels of pentosidine. The exponential age-related increase in pentosidine observed in both types of penile tissue suggests an impairment of collagen turnover, which could be related to the advanced glycation reaction in aging. It is not known whether pentosidine itself is directly associated with erectile dysfunction, but its formation is usually accompanied by extensive tissue modification. Formation of advanced Maillard reaction products, which is greatly accelerated in aging, diabetes, and uremia, could contribute to erectile dysfunction in these syndromes.
Adult↗
Radical AGEing in Alzheimer's disease.
The pathological presentation of Alzheimer's disease, the leading cause of senile dementia, involves regionalized neuronal death and an accumulation of intracellular and extracellular filamentous protein aggregates that form lesions termed neurofibrillary tangles and senile plaques, respectively. Several independent parameters have been suggested as the primary factor that is responsible for this pathogenesis, including apolipoprotein epsilon genotype, hyperphosphorylation of cytoskeletal proteins, or metabolism of amyloid beta. However, at present, no one theory explains adequately the host of complex biochemical and pathological facets of the disease. Recent findings suggest that age-related increases in oxidative stress and protein glycation either individually, or more probably in a synergistic manner, could, exclusive of the other theories or in concert with them, account for all aspects of Alzheimer's disease.
Aging↗
Influence of dialysis modality on plasma and tissue concentrations of pentosidine in patients with end-stage renal disease.
Plasma and tissue concentrations of pentose-derived glycation end-products ("pentosidine") are elevated in diabetic patients with normal renal function and in both diabetic and nondiabetic patients with end-stage renal disease. To determine the influence of dialysis modality and other clinical variables on the accumulation of pentosidine, we used high-performance liquid chromatography to measure this advanced glycation end-product in plasma, skin, and peritoneal samples obtained from 65 hemodialysis and 45 peritoneal dialysis patients. Plasma pentosidine levels were significantly lower in peritoneal dialysis patients. Concentrations of pentosidine in skin were similar in the two groups. In contrast, peritoneal concentrations of pentosidine were significantly higher in the patients maintained on peritoneal dialysis. Our results demonstrate that dialysis modality influences the plasma and tissue distribution of pentosidine. Compared with hemodialysis, peritoneal dialysis is associated with lower levels of this glycation end-product in plasma, but with higher levels in the peritoneum. The mechanisms accounting for lower circulating levels of pentosidine in peritoneal dialysis patients remain to be determined. Higher levels in peritoneal tissues may reflect chronic exposure to the high concentrations of glucose in peritoneal dialysate.
Arginine↗
Advanced Maillard reaction end products, free radicals, and protein oxidation in Alzheimer's disease.
Explore the source record for details and available documents.
Alzheimer Disease↗
Isolation, purification, and characterization of an Amadori product binding protein from a Pseudomonas sp. soil strain.
Sugars react nonenzymatically with protein amino groups to form a ketoamine adduct (Amadori product), which leads to the formation of advanced glycation end-products. These compounds are involved in the development of tissue modifications such as cross-linking and fluorescence in diabetes and aging. Searching for an enzyme to reverse protein glycation, we isolated a Pseudomonas sp. soil strain growing selectively on the Amadori product epsilon-fructosyl-aminocaproate. An Amadori product binding protein (ABP) was purified from the bacterial extract by single-step affinity chromatography on glycated lysine-Sepharose. The protein, a monomer of 45 kDa, did not bind to unglycated or NaBH4-reduced glycated lysine-Sepharose suggesting specificity for the Amadori compound. The concentration-dependent binding of glycated aminocaproate showed saturation with Kd = 1.49 microM and Bmax = 17.63 nmol/mg of protein corresponding to 0.8 mol/mol of protein. The binding of epsilon-1-[14C]fructosyl-aminocaproate to the protein was inhibited by other glucose-derived Amadori products, but not by free sugars, unglycated amines, or ribated lysine. The sequence of the first 16 NH2-terminal amino acids and a GenBank search revealed that ABP is a novel protein. Its synthesis was inducible by growth of the organism in Amadori product. Immunoblotting studies showed that ABP is not found in cell extracts from other prokaryotes, yeast, or liver homogenate and does not bind Amadori products in glycated proteins. ABP has no enzymatic activity toward glycated substrates and may thus have transport or permease function for glycated amino acids.
Amino Acid Sequence↗
Advanced Maillard reaction end products are associated with Alzheimer disease pathology.
During aging long-lived proteins accumulate specific post-translational modifications. One family of modifications, termed Maillard reaction products, are initiated by the condensation between amino groups of proteins and reducing sugars. Protein modification by the Maillard reaction is associated with crosslink formation, decreased protein solubility, and increased protease resistance. Here, we present evidence that the characteristic pathological structures associated with Alzheimer disease contain modifications typical of advanced Maillard reaction end products. Specifically, antibodies against two Maillard end products, pyrraline and pentosidine, immunocytochemically label neurofibrillary tangles and senile plaques in brain tissue from patients with Alzheimer disease. In contrast, little or no staining is observed in apparently healthy neurons of the same brain. The Maillard-reaction-related modifications described herein could account for the biochemical and insolubility properties of the lesions of Alzheimer disease through the formation of protein crosslinks.
Alzheimer Disease↗
Suppression of pentosidine formation in galactosemic rat lens by an inhibitor of aldose reductase.
Recent work from our laboratory revealed a correlation between the degree of protein pigmentation in human cataractous lens and the advanced Maillard reaction as reflected by pentosidine formation. Although the data suggested a role for ascorbate in pentosidine formation in senile cataractous lenses, elevated pentosidine levels in diabetic cataracts suggested that glucosylation may be involved directly in pentosidine biosynthesis. To clarify this issue, we quantified pentosidine in lenses from rats with experimental galactosemia with and without aldose reductase inhibitor treatment. At 12 months, pentosidine-like fluorescence (335/385 nm) was three to six times higher (P < 0.0001) in water soluble and insoluble crystallins of galactosemic compared with nongalactosemic rats. Actual pentosidine levels increased shortly after onset of galactosemia. Contents in water-insoluble crystallins were 6.32 +/- 2.2 and 1.40 +/- 0.66 pmol/mg protein in galactosemic and control lenses, respectively (P < 0.001). Fluorescence and pentosidine were suppressed to almost control levels upon treatment with sorbinil. Incubation experiments showed that pentosidine could form slowly from galactose, but much more rapidly from ascorbate and its oxidation products. Its formation could be inhibited partly by both reduced and oxidized glutathione or epsilon-aminocaproic acid. The requirement of oxygen for pentosidine formation suggests that oxidative stress associated with glutathione depletion and ascorbate oxidation are plausible mechanisms for rapid pentosidine formation upon onset of galactosemia. In contrast, Maillard reaction by glycoxidation products may account for the sustained increase in pentosidine. Both these events may be linked to the newly recognized pseudohypoxic state of cells exposed to high sugar concentrations.
Aldehyde Reductase↗
[The role of glucose in the pathogenesis of diabetes complications].
Explore the source record for details and available documents.
Aldehyde Reductase↗
ELISA of pentosidine, an advanced glycation end product, in biological specimens.
Pentosidine is a fluorescent protein cross-link and glycoxidation marker for the advanced glycation reaction in diabetes, aging, and uremia. We raised polyclonal antibodies in New Zealand White rabbits against this hapten coupled to keyhole limpet hemocyanin. The antibodies detected by ELISA reacted strongly with free pentosidine but not with pentosidine-like compounds. The working range of the competitive ELISA for standard pentosidine was 0.1-100 pmol. Pentosidine was detectable in bovine serum albumin incubated with ribose as a function of incubation time. Immunoblotting studies showed that pentosidine specifically stained in oligomers of lysozyme incubated with ribose. Digestion with protease (Pronase E, 20 g/kg) as well as acid hydrolysis enhanced the immunoreactivity of samples, the pentosidine values in digested human plasma correlating with those measured by HPLC (r = 0.98). Pentosidine in diabetic and uremic plasma digested with Pronase E was significantly higher than normal (P < 0.01; mean +/- SD): 1620 +/- 1940 and 2630 +/- 1320 [corrected] nmol/L, respectively, vs 151 +/- 55 nmol/L (normal). Amounts of pentosidine in hydrolyzed skin collagen increased with age and were increased in diabetes and uremia. This ELISA provides a new tool for assessing the role of the advanced Maillard reaction in aging and age-related diseases.
Animals↗
Differential effects of type 2 (non-insulin-dependent) diabetes mellitus on pentosidine formation in skin and glomerular basement membrane.
Pentosidine is an advanced Maillard/glycation reaction product the formation of which in human skin is significantly increased in Type 1 (insulin-dependent) diabetes mellitus and correlates with the severity of diabetic complications. Preliminary data in a limited number of Type 2 (non-insulin-dependent) diabetic individuals showed that skin pentosidine was not significantly elevated, raising the question of whether statistical power was insufficient for differences to be revealed, or whether pentosidine did not form because biological factors intrinsic to Type 2 diabetes affected the advanced Maillard reaction altogether. To resolve this question, pentosidine levels were measured in 209 human skin samples obtained at autopsy and in purified glomerular basement membranes from 45 subjects of various ages, with and without Type 1 and Type 2 diabetes and uraemia. Pentosidine increased exponentially in skin but curvilinearly in glomerular basement membranes, and reached 75 and 50 pmol/mg collagen at projected 100 years, respectively. Skin levels were not significantly elevated in individuals with Type 2 diabetes (p > 0.05). In contrast, pentosidine levels in glomerular basement membranes were elevated above the 95% confidence interval in the majority of diabetic patients regardless of the type of diabetes and in all individuals on haemodialysis. These data clearly demonstrate that the advanced Maillard reaction is indeed accelerated in Type 2 diabetes and strongly suggest that differences in pentosidine accumulation rates may be due to differences in collagen turnover. In diabetes and uraemia, accelerated Maillard reaction mediated protein crosslinking, as reflected by pentosidine, may contribute to decreased turnover of the extracellular matrix, sclerosis and thickening of basement membranes.
Adult↗
Effects of kidney or kidney-pancreas transplantation on plasma pentosidine.
Tissue and plasma concentrations of pentose-derived glycation end-products ("pentosidine") are elevated in diabetic patients with normal renal function and in both diabetic and nondiabetic patients with end-stage renal disease. To determine the effects of correcting hyperglycemia and/or renal failure on the accumulation of pentosidine, we used reverse phase and ion exchange high performance liquid chromatography to measure this advanced glycation end-product in plasma proteins of diabetic and nondiabetic transplant recipients at various time intervals after kidney-pancreas or kidney transplantation. Changes in plasma pentosidine levels after transplantation were compared to changes in simultaneously obtained glycohemoglobin levels. Both kidney and kidney-pancreas transplantation were accompanied by a dramatic, but incomplete, reduction of plasma pentosidine concentrations within three months of transplantation. Kidney-pancreas transplantation resulted in normal glycohemoglobin levels within three months but offered no advantage over kidney transplantation alone in the partial correction of plasma pentosidine levels. There was no correlation between posttransplant plasma pentosidine and glycohemoglobin levels in either diabetic or nondiabetic transplant recipients. We conclude that renal failure is the major factor accounting for the accumulation of pentosidine in both diabetic and nondiabetic patients with end-stage renal disease. Restoration of euglycemia after kidney-pancreas transplantation provides no additional benefit in reducing plasma pentosidine levels to that achieved by correction of renal failure after kidney transplantation alone.
Adult↗
Relevance of the early and advanced Maillard reaction in diabetic neuropathy.
Explore the source record for details and available documents.
Animals↗
Isolation and characterization of a blue fluorophore from human eye lens crystallins: in vitro formation from Maillard reaction with ascorbate and ribose.
A blue fluorophore, named LM-1 was isolated from human eye lens crystallins. The fluorescence property of LM-1 (excitation/emission, 366/440 nm) is similar to the fluorescence originating during non-enzymatic glycation (Maillard reaction) of proteins with the reducing sugars. LM-1 accumulates linearly with age in highly cross-linked water insoluble crystallins and is present at higher levels in cataractous lenses. The fluorophore could be synthesized by incubation of bovine serum albumin (BSA) with ribose, but not with glucose or fructose. Incubation of bovine lens crystallins with ascorbic acid (ASA) and its oxidative products, dehydroascorbic acid (DHA) and 2,3-diketogulonic acid (DKG) in presence of oxygen resulted in LM-1 formation. When oxygen was removed from the system, only DHA and DKG could synthesize LM-1, but not ASA, suggesting that ASA oxidation is obligatory for LM-1 synthesis. Modification of lysine residues on BSA prior to incubation with ribose resulted in corresponding decrease in LM-1 formation. Since ASA concentration is unusually high in lens and has been found to be a powerful glycating agent of crystallins and since LM-1 does not form with hexoses, it is likely that ASA is the major precursor of LM-1.
Adult↗