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PubMed1991

Binding of ubiquitin to experimentally induced murine AA amyloid.

Amyloid enhancing factor (AEF) activity has recently been demonstrated in ubiquitin purified from amyloidotic murine tissues and Alzheimer brain extract. Since AEF is known to bind to amyloid fibrils and 'fibril-AEF' on passive transfer induces accelerated amyloidogenesis in the recipient animals, it was of interest to investigate whether ubiquitin binds to amyloid. Immunohistological studies were carried out on liver sections from amyloidotic mice. Biotin-strepavidin-peroxidase methods using monospecific rabbit anti-mouse AA amyloid IgG (RAAG) and rabbit anti-bovine ubiquitin IgG (RABU) antibodies were employed to immunostain the amyloid and ubiquitin deposits, respectively. RABU-treated liver sections were counterstained with thioflavine S. RAAG reacted strongly with the amyloid, indicating that it is AA type, and RABU-positive immunodeposits were found bound to the thioflavine-S-positive AA deposits. Treatment of the liver sections with 0.1 M sodium acetate containing 0.5 M NaCl, pH 4, for 2-3 h at 37 degrees C nearly completely desorbed the AA amyloid-bound ubiquitin. Since ubiquitin demonstrates AEF activity in vivo and binds non-covalently to AA amyloid, we suggest that ubiquitin may indeed be 'fibril-AEF' and may play a crucial role in the pathogenesis of amyloidosis. To our knowledge, this is the first time that ubiquitin bound to extracellularly deposited amyloid has been demonstrated.

Animals↗
PubMed1994

Ubiquitin profile in inflammatory leukocytes and binding of ubiquitin to murine AA amyloid: immunocytochemical and immunogold electron microscopic studies.

Lysosomes in activated murine monocytoid cells have been implicated in AA amyloid formation. The pathophysiology of this process is not well understood. Previous studies into the nature of the relationship between ubiquitin (UB), possessing intrinsic amyloid enhancing factor (AEF) activity; serum amyloid A (SAA), the precursor protein of AA amyloid; and activated monocytoid cells have indicated a temporal and spatial relationship between these proteins and tissue AA amyloid deposits. To extend these findings, we have examined murine peritoneal leukocytes and splenic tissues during the early amyloid deposition phase by immunocytochemical and immunogold electron microscopic methods using monospecific anti-ubiquitin and anti-mouse AA amyloid antibodies. We show here enrichment of endosome-lysosome-like (EL) vesicles in the activated monocytoid cells with UB and SAA, and the presence of UB-bound AA amyloid fibrils in the EL vesicles, perikarya, and interstitial spaces. The importance of these findings is emphasized by the fact that activated monocytoid cells, containing UB in the EL vesicles, sequester and eventually localize SAA in their EL vesicles, and that UB binds to the EL-contained AA amyloid fibrils. These findings may also have functional consequences for studies on the role of EL and UB in amyloidogenesis.

Amyloidosis↗
PubMed2006

Liquid chromatography/tandem mass spectrometry characterization of oxidized amyloid beta peptides as potential biomarkers of Alzheimer's disease.

Alzheimer's disease is characterized by the deposition of senile plaques that consist primarily of amyloid beta peptides. There is substantial evidence that amyloid beta is oxidized in vivo, which has led to the suggestion that oxidative stress is an important mediator of Alzheimer's disease. Metal-catalyzed oxidation can mimic in vivo oxidation of amyloid beta because the metal ion binds to the amino acid residues at the site of oxidation, which then deliver reactive oxygen species to that site. Based on electrospray mass spectrometry, it has been suggested that metal-catalyzed oxidation occurs on histidines-13 and -14. Unfortunately, the amyloid beta peptides provide complex spectra, so it is difficult to definitively characterize the sites of oxidation. Trypsin digestion of both native and oxidized amyloid beta1-16 and amyloid beta1-40 resulted in the formation of tryptic peptides corresponding to amyloid beta6-16, which could be separated by liquid chromatography (LC). Sites of oxidation were then unequivocally characterized as histidine-13 and histidine-14 by LC/tandem mass spectrometric (MS/MS) analysis of the tryptic peptides. The ability to analyze the specific amyloid beta6-16 tryptic fragments derived from full-length amyloid beta peptides will make it possible to determine whether oxidation in vivo occurs at specific histidine residues and/or at other amino acid residues such as methionine-35. Using methodology based on LC/MS/MS it will also be possible to analyze the relative amounts of oxidized peptides and native peptide in cerebrospinal fluid from patients with Alzheimer's disease as biomarkers of oxidative stress.

Alzheimer Disease↗
PubMed1996

Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine.

It is well known that beta-amyloid accumulates abnormally in Alzheimer's disease; however, beta-amyloid's relationship to cognitive dysfunction has not been clearly established and is often confounded by the presence of neurofibrillary tangles. We used canines to investigate the relationship between beta-amyloid accumulation and cognitive function in an animal model of aging lacking neurofibrillary tangles. The performance of 20 canines (11 purebred beagles and 9 mongrels) on a battery of six cognitive tasks was measured. These tasks included Reward Approach and Object Approach learning, as well as Discrimination, Reversal, Object Recognition, and Spatial learning and memory. Aged canines were impaired on some tasks but not others. beta-Amyloid-immunopositive plaques were found in many of the older animals. Plaques were all of the diffuse subtype and many contained intact neurons detected with double-labeling for neurofilaments. No neurofibrillary tangles were detected. beta-Amyloid was also associated with the processes of many neurons and with blood vessels. Using computerized image analysis, we quantified the area occupied by beta-amyloid in entorhinal cortex, frontal cortex, and cerebellum. Controlling for age-related increases in beta-amyloid, we observed that increased beta-amyloid deposition is strongly associated with deficits on Discrimination learning (r = .80), Reversal learning (r = .65), and Spatial learning (r = .54) but not the other tasks. There were a few differences between breeds which are discussed in the text. Overall, these data suggest that beta-amyloid deposition may be a contributing factor to age-related cognitive dysfunction prior to the onset of neurofibrillary tangle formation.

Alzheimer Disease↗
PubMed2002

Antibody to amyloid beta protein alleviates impaired acquisition, retention, and memory processing in SAMP8 mice.

SAMP8 (senescence-accelerated mouse, P8 strain) mice overproduce amyloid precursor protein and beta-amyloid and have learning and memory deficits. Preliminary data have indicated that overproduction of beta-amyloid plays a role in the pathogenesis of acquisition and retention deficits in SAMP8 mice. In the studies reported here, the authors examined the effects of polyclonal and monoclonal antibodies to beta-amyloid on acquisition and retention in an aversive T-maze testing paradigm when injected intracerebroventricularly (ICV) into 12-month SAMP8/TaJF mice. Both the polyclonal and monoclonal antibodies improved acquisition and retention when injected ICV 1 to 14 days prior to acquisition testing. Injection of all three antibodies intrahippocampally immediately following training improved retention on the T-maze when mice were tested 7 days later. The authors next studied the effect of monoclonal beta-amyloid antibody injected 48 h prior to training on the effect on retention in the T-maze of drugs modulating classical neurotransmitters. Arecoline and glutamate were injected directly into the hippocampus, and ketanserin, methiothepen, bicuculline, and OH-saclofen were injected into the septum. Previously, the authors have found that the doses of these drugs required to improve retention are markedly altered in 12-month SAMP8/TkJF mice compared to 4-month P8 mice. In these studies, it was demonstrated that antibody to beta-amyloid resulted in these drugs improving retention at doses that improved memory in 4-month SAMP8/TaJF mice. Based on these findings, we conclude that beta-amyloid overproduction is at least in part responsible for the acquisition and memory deficits in 12-month-old SAMP8/TaJF mice. Antibody to beta-amyloid restores the retention response to neurotransmitter manipulation to that seen in 4-month-old mice. beta-amyloid appears to play a key role in the loss of acquisition and retention seen in SAMP8/TaJF mice.

Amyloid beta-Peptides↗
PubMed1991

Nucleoside diphosphatase (NDPase) activity associated with human beta-protein amyloid fibers.

Nucleoside diphosphatase (NDPase) activity was studied by electron microscope cytochemistry in surgical specimens obtained from aged human cerebral cortices. The presence of NDPase activity on the surface of the microglial cells (MCs) and especially within the endoplasmic reticulum (ER) cisternae that are filled with amyloid fibers and that are in continuity with the extracellular amyloid deposits in plaques suggests a possible role of this enzyme in final elaboration of amyloid protein. The close structural relationship between MCs and amyloid plaques, suggesting the participation of these cells in the synthesis or final elaboration of amyloid fibers, was observed. The comparison of these observations with previously reported data on the distribution of NDPase in MCs and amyloid fibers in scrapie-infected mouse brain suggests that presumably similar mechanisms are acting in both cases. These observations, as compared with the results of other cytochemical and biochemical studies, also suggest that co-localization of NDPase activity with newly formed amyloid fibers in plaques can be associated with glycosyltransferase activities engaged in the amyloid or amyloid precursor protein glycosylation.

Acid Anhydride Hydrolases↗
PubMed1984

Clinical value of immunohistochemistry with AF-antibody in the diagnosis of familial amyloid neuropathy.

Peripheral polyneuropathy associated with recurrent diarrhoea and orthostatic hypotension was observed in two unrelated German kinships and two sporadic cases. Congo red staining and polarization microscopy of biopsy specimens revealed amyloid deposits. Immunohistochemical investigation using the indirect immunoperoxidase staining with antisera to several purified amyloid fibril proteins showed a positive reaction with an antiserum to the prealbumin-related AF-amyloid in the families and one of the sporadic cases and with an antiserum to the immunoglobulin light chain amyloid (A lambda) in the other sporadic case. Therefore, the amyloid of the families and one of the sporadic cases was identified as the prealbumin-related AF amyloid, while the amyloid of the other sporadic case was of immunoglobulin origin. It is concluded that immunohistochemistry with antisera to the different amyloid proteins is useful in the differential diagnosis of amyloid neuropathy.

Adult↗
PubMed1988

Renal amyloidosis. Correlations between morphology, chemical types of amyloid protein and clinical features.

Sixty-one autopsy cases of renal amyloidosis were reviewed to assess the relationship of renal pathology to chemical types of amyloid and clinical features. Glomerular amyloid deposition was divided on the basis of morphological characteristics, into four types: a mesangial nodular type showing nodular mesangial deposits with sparse capillary wall involvement (25 cases), a mesangio-capillary type disclosing diffuse amyloid deposition in the mesangium and along both sides of the glomerular basement membrane (19 cases), a perimembranous type principally involving the subepithelial side of the basement membrane invariably characterized by exuberant spicular arrangement (6 cases), and a hilar type showing amyloid deposits almost exclusively in hilar arterioles (11 cases). Twenty-four of 25 cases of mesangial nodular type (96%) showed amyloid protein of AA type. However, mesangio-capillary and perimembranous types were associated with deposition of AL amyloid protein in 15 of 19 (79%) and all 6 cases, respectively. Nephrotic syndrome was more frequent in patients with AL amyloidosis; notably, all patients with perimembranous type had nephrotic syndrome irrespective of the extent of glomerular amyloid deposits. Chronic renal failure and renal death appeared more common in mesangial nodular type in which the extent of glomerular amyloidosis correlated with that of vascular amyloid deposits. The results obtained suggest that the chemical type of glomerular amyloid protein (AA vs AL) is associated with significant differences in the morphological, clinical and prognostic features of the renal involvement.

Adult↗
PubMed1989

Influence of serum amyloid A on cholesterol esterification in human plasma.

Lecithin-cholesterol acyltransferase (EC 2.3.1.43, LCAT) is the enzyme responsible for the formation of the bulk of cholesteryl ester in human plasma. The LCAT-reaction takes place mainly on high-density lipoproteins and requires an apolipoprotein as activator. Besides apolipoprotein (apo) A-I several other potent activator apolipoproteins (AIV, E and CI) were identified, furthermore apo A-II was shown to be a modulator of the enzyme's reaction in the presence of apo A-I. Serum amyloid A, an apolipoprotein mainly associated with high-density lipoprotein, massively accumulates in plasma upon acute phase reactions. We therefore studied the possible influence of this acute phase reactant on cholesterol esterification in human plasma. There was a significant decrease of esterified cholesterol in plasma during acute phase reaction. We found a highly significant correlation between the unesterified part of plasma cholesterol and serum amyloid A levels (r = 0.694, P = 0.0001). Also, plasma LCAT activity was negatively correlated with serum amyloid A levels. Lipoproteins containing apo A-I and A-II (LpA-I: A-II) and lipoproteins containing apo A-I but no A-II (LpA-I) decreased significantly with the appearance in plasma of serum amyloid A. To study the influence of serum amyloid A on the LCAT reaction, artificial substrates were prepared either by a detergent dialysis procedure or by addition of apolipoprotein to a sonicated aqueous dispersion of lipid. In addition two different molar ratios of apolipoprotein/phospholipid (PC) (1:50 and 1:310) were chosen at a constant molar ratio of total cholesterol/PC of 1:20. The various substrates were incubated with purified LCAT enzyme. DMPC - or egg yolk phosphatidylcholine - cholesterol-[4-14C]cholesterol-serum amyloid A complexes per se did not stimulate LCAT activity significantly. However, apo serum amyloid A incorporated together with apo A-I by a detergent dialysis procedure lead at low concentrations of serum amyloid A to a marked increase in cholesteryl ester formation as compared to apo A-I alone but inhibited the cholesteryl ester formation at high concentrations. Thus, the low levels of esterified cholesterol in acute phase plasma are to some extent due to decreased plasma enzyme activity and in part may be due to interference of apo serum amyloid A with the natural substrate complexes of plasma HDL.

Acute-Phase Reaction↗
PubMed1988

Immunohistochemical study of Alzheimer's disease using antibodies to synthetic amyloid and fibronectin.

Etiology and source of amyloid deposition in senile plaques of Alzheimer's disease (AD) are still unknown. In order to know whether or not fibronectin (Fn), an adhesive glycoprotein, is related to the amyloid deposition in the senile plaque, we conducted immunohistochemical studies using polyclonal anti-Fn and affinity-purified anti-amyloid component (Affi 28). Affi 28 was made by immunizing a rabbit against the synthetic peptide corresponding to residues 1-28 of the amyloid core protein reported by Masters et al. (1985). According to this study, four points became clear. First, Affi 28 is able to stain the subpial regions of AD as well as cerebrovascular amyloid and amyloid plaque cores. Second, it is suggested either that the etiology and source of neurofibrillary tangles and Pick body is distinct from that of the senile plaque or that any Affi 28 determinants of neurofibrillary tangles and Pick body are obscured sterically. Third, Affi 28 is useful to distinguish the senile plaque from the amyloid plaque of Creutzfeldt-Jakob disease. Last, there is no association between the amyloid in the senile plaque and Fn, at least immunohistochemically. The absence of Fn in the senile plaque suggests that Fn may not be requested for the deposition of amyloid fibrils.

Alzheimer Disease↗
PubMed1994

Cathepsin G: localization in human cerebral cortex and generation of amyloidogenic fragments from the beta-amyloid precursor protein.

Amyloid deposits in Alzheimer's disease, Down's syndrome and aged brain are composed largely of A beta protein, which is generated by proteolytic processing of beta-amyloid precursor protein. Proteases responsible for liberating the A beta protein from the precursor have not yet been identified. Here, we examined the ability of cathepsin G, a chymotrypsin-like protease, to cleave two protease substrates: (i) a fluorogenic hexapeptide, whose sequence spans the cleavage site in the precursor for generating the A beta NH2-terminus, and (ii) recombinant human beta-amyloid precursor protein purified from a baculovirus expression system. Unlike two other members of the chymotrypsin family, cathepsin G readily degraded the hexapeptide. Furthermore, cathepsin G cleaved the beta-amyloid precursor protein to generate several breakdown products, including a prominent 11,500 mol. wt fragment immunoreactive with antibodies directed against the COOH-terminus of the protein. This COOH-terminal fragment co-migrated using two-dimensional isoelectric focusing/sodium dodecyl sulfate-polyacrylamide gel electrophoresis with C-100, a recombinant COOH-terminal segment of the beta-amyloid precursor, whose NH2-terminus is one residue upstream of the NH2-terminus of the A beta domain. We also examined the localization of cathepsin G in human brain. The distribution of cathepsin G-containing cells was examined by immunohistochemistry in the temporal cortex of both Alzheimer's and aged control samples. Cathepsin G-like immunoreactivity was contained specifically within neutrophils. As visualized by double-labeling with antibodies to cathepsin G and Factor VIII, neutrophils were most frequently found within meningeal or cortical blood vessels. In addition, occasional neutrophils could be identified without an apparent vascular surround, in the brain parenchyma. By simultaneous labeling with antibodies to cathepsin G and A beta protein, neutrophils were also sometimes found associated with both parenchymal and vessel amyloid deposits; however, these associations were rare. These findings indicate that cathepsin G is capable of cleaving the beta-amyloid precursor protein to liberate the free NH2-terminus of the A beta protein and may have access to areas where this material is deposited in Alzheimer's disease. However, since there is no physical association between neutrophils and deposited amyloid and no increase in the number of neutrophils in an Alzheimer's brain, cathepsin G seems to be an unlikely mediator of amyloid deposition in this disease.

Alzheimer Disease↗
PubMed1995

Differential regulation by beta-amyloid peptides of intracellular free Ca2+ concentration in cultured rat microglia.

We have previously shown that exposure to beta-amyloid peptides alters microglial activity and viability. It is thought that beta-amyloid peptides induce toxicity in neuronal cultures by destabilizing Ca2+ homeostasis. To investigate the effects of beta-amyloid peptides on intracellular free Ca2+ concentration ([Ca2+]i) in cultured microglia, we used Fura-2 imaging. Exposure to 25 microM beta-amyloid-(25-35) induced increases in 2+]i within 1 h. In contrast, exposure to 25 microM beta-amyloid-(1-42), the full-length homolog to the beta-amyloid protein deposited in plaques, does not, over the same time period. However, the average [Ca2+]i of microglia is increased by a 6 h exposure to beta-amyloid-(1-42). Thus, beta-amyloid-(25-35) can alter [Ca2+]i in microglia on a different time scale than beta-amyloid-(1-42), indicating a specificity in the response of these cells as compared to neurons.

Amyloid beta-Peptides↗
PubMed2007

Glucose- and time-dependence of islet amyloid formation in vitro.

Islet amyloid contributes to the loss of beta-cell mass in type 2 diabetes. To examine the roles of glucose and time on amyloid formation, we developed a rapid in vitro model using isolated islets from human islet amyloid polypeptide (hIAPP) transgenic mice. Islets from hIAPP transgenic and non-transgenic mice were cultured for up to 7 days with either 5.5, 11.1, 16.7 or 33.3mmol/l glucose. At various time-points throughout the culture period, islets were harvested for determination of amyloid and beta-cell areas, and for measures of cell viability, insulin content, and secretion. Following culture of hIAPP transgenic islets in 16.7 or 33.3mmol/l glucose, amyloid formation was significantly increased compared to 5.5 or 11.1mmol/l glucose culture. Amyloid was detected as early as day 2 and increased in a time-dependent manner so that by day 7, a decrease in the proportion of beta-cell area in hIAPP transgenic islets was evident. When compared to non-transgenic islets after 7-day culture in 16.7mmol/l glucose, hIAPP transgenic islets were 24% less viable, had decreased beta-cell area and insulin content, but displayed no change in insulin secretion. Thus, we have developed a rapid in vitro model of light microscopy-visible islet amyloid formation that is both glucose- and time-dependent. Formation of amyloid in this model is associated with reduced cell viability and beta-cell loss but adequate functional adaptation. It thus enables studies investigating the mechanism(s) underlying the amyloid-associated loss of beta-cell mass in type 2 diabetes.

Amyloid↗
PubMed2006

Amyloid fibril formation propensity is inherent into the hexapeptide tandemly repeating sequence of the central domain of silkmoth chorion proteins of the A-family.

Peptide-analogues of the A and B families of silkmoth chorion proteins form amyloid fibrils under a variety of conditions [Iconomidou, V.A., Vriend, G. Hamodrakas, S.J. 2000. Amyloids protect the silkmoth oocyte and embryo. FEBS Lett. 479, 141-145; Iconomidou,V.A., Chryssikos, G.D.,Gionis, V., Vriend, G., Hoenger, A., Hamodrakas, S.J., 2001. Amyloid-like fibrils from an 18-residue peptide-analogue of a part of the central domain of the B-family of silkmoth chorion protein. FEBS Lett. 499, 268-273; Hamodrakas, S.J. Hoenger, A., Iconomidou, V. A., 2004 . Amyloid fibrillogenesis of silkmoth chorion protein peptide-analogues via a liquid crystalline intermediate phase. J. Struct. Biol. 145, 226-235.], which led us to propose that silkmoth chorion is a natural protective amyloid. In this study, we designed and synthesized two mutant peptide-analogues of the central conservative domain of the A family: (a) one, cA_m1, with a length half of that of the central domain of the A family, which folds and self-assembles, in various conditions, into amyloid fibrils very similar in properties and structure to the fibrils formed by the cA peptide, which corresponds to the entire length of the A family central domain [Iconomidou, V.A., Vriend, G. Hamodrakas, S.J. 2000. Amyloids protect the silkmoth oocyte and embryo. FEBS Lett. 479, 141-145.], in full support of our previous proposal, (b) the second, cA_m2, differing from cA_m1 at three positions, where three glutamates have replaced two valines and one alanine residues, does not form amyloid fibrils in any conditions. It appears that (a) the amyloidogenic properties of silkmoth chorion peptides are encoded into the tandemly repeating hexapeptides comprising the central domain of silkmoth chorion proteins, and, that (b) suitable mutations, properly and carefully designed, greatly affect the strong amyloidogenic properties inherent in certain aminoacid sequences and may inhibit amyloid formation.

Amino Acid Motifs↗
PubMed2005

Influence of tissue fixation on the microextraction and identification of amyloid proteins.

In surgical pathology, correct immunohistochemical identification of AL amyloidosis poses a particular problem. Immunostaining for lambda- or kappa-light chains is commonly encountered even in non-immunoglobulin-derived amyloidoses, which leads to a false-positive classification as AL amyloidosis. In this respect, microextraction of amyloid proteins from surgical pathology specimens and their subsequent biochemical characterization may prove useful in reaching the correct diagnosis. In this study, we investigated systematically the influence of fixation on the extraction of amyloid proteins from amyloid-containing tissue samples. Tissue samples were obtained from a patient with generalized AA amyloidosis and from a second patient with generalized AL amyloidosis. The samples were stored either unfixed or fixed in phosphate buffered 4% p-formaldehyde, methacarn, or Bouin for 3 days, 1 week, or 1 month. Thereafter, proteins were extracted according to the procedure of Layfield et al, separated by SDS-PAGE and subjected to Western blotting, using antibodies directed against AA amyloid and immunoglobulin-derived lambda-light chain. Following this procedure, a variety of differently sized AA amyloid or lambda-light chain immunoreactive protein bands were found in both patients, which is typical for amyloid proteins. Fixation time did not per se prohibit the extraction of these amyloid proteins from tissue samples, which remained detectable irrespective of fixation time. Although all three fixatives impaired the resolution of some, but not all, individual amyloid proteins, this procedure may help to confirm or reject a diagnosis of AL amyloidosis, because detection of several lambda- or kappa-light chain immunoreactive protein bands in the low-molecular-weight range (<20 kDa) is a common characteristic of their amyloid nature.

Amyloid↗
PubMed2005

Alzheimer's disease and the 'ABSENT' hypothesis: mechanism for amyloid beta endothelial and neuronal toxicity.

Alzheimer's disease [AD] is the most common cause of dementia among people age 65 and older. One of the biggest stumbling blocks in developing effective drug therapy for Alzheimer's disease has been the lack of a comprehensive hypothesis that explains the mechanism behind all of the histopathological changes seen in patients suffering from Alzheimer's disease. An overview of the currently popular 'amyloid' and 'vascular' hypotheses for AD demonstrates that neither hypothesis by itself can explain all the known histopathological and biochemical lesions seen in Alzheimer's disease. The paper presents a hypothesis that tries to explain the mechanism behind almost all the histopathological changes, and varying clinical manifestations seen in both diagnosed AD and Vascular Dementia [VaD]. The new hypothesis is based on the known dual toxicity of beta amyloid to both vascular and neuronal tissues, their synergy and the resultant net effect on the onset and progression of AD. The new hypothesis therefore will be known as the Amyloid Beta Synergistic Endothelial and Neuronal Toxicity [ABSENT] hypothesis. The ABSENT hypothesis will try to show the common chemical mechanism behind almost all of the pathological changes seen in AD. According to the ABSENT hypothesis, beta amyloid itself generates all the free radicals that cause both vascular dysfunction and the neuronal damage seen in AD. The chemical mechanism proposed is based on evidence from physical chemistry experiments, calculations as well as in vitro/in vivo experiments. The ABSENT hypothesis does not favor one mode of beta amyloid-induced brain damage over the other, rather it considers the net effects of the neuronal stress/damage caused by both the cerebrovascular dysfunction and direct neurotoxicity caused by beta amyloid. The hypothesis states that each patient has a different balance of predisposing factors that modulate the extent of neurotoxicity and cerebrovascular dysfunction caused by beta amyloid and thereby explains the wide range and mixed nature of damage and dysfunction seen in the studies done on patients diagnosed with AD, VaD or 'mixed dementias'. According to the hypothesis, beta amyloid peptides are necessary if not sufficient to cause AD, VaD and mixed senile dementias. The hypothesis, therefore, proposes the term Beta Amyloid Dementias [BAD] to describe the conditions currently covered by the diagnoses of 'AD', 'VaD' and 'Mixed [senile] Dementias'. Finally, the ABSENT hypothesis tries to put forth a direct chemical mechanism behind the apparent synergy and increased association between old age, pre- and coexisting vascular disease, diabetes and AD.

Aged↗
PubMed2005

Protective effect of colostrinin on neuroblastoma cell survival is due to reduced aggregation of beta-amyloid.

Colostrinin (CLN), a mixture of proline-rich polypeptides, has shown a stabilizing effect on cognitive function in Alzheimer's patients measured by the Alzheimer's disease Assessment Scale-cognitive (ADAS-cog) and in Instrumental Activities of Daily Living (ILDL) in recently conducted clinical trials. The aim of this study was to elucidate a possible mode of action of CLN in the treatment of Alzheimer's disease. Here, we report that CLN prevents the aggregation of beta-amyloid peptide Abeta (1-40) in vitro. The impact of CLN on the fibril formation was monitored by optical and electron microscopy. The electron micrographs illustrate that, at 25 microM, Abeta (1-40) peptides formed fibrils after 24-48 h of incubation. The presence of 0.25 microM CLN completely abolished the fibril formation. Abeta (1-40) peptides grow into dense fibers when examined at the 20th day. In the presence of CLN, however, the fibrils are much shorter and less dense. Addition of CLN as late as the 17th day can still dissolves the preformed fibrils. These observations were compared to the effect of CLN on the neurotoxic activity of beta-amyloid peptides in the cell culture model (SHSY-5Y). The beta-amyloid peptides were pre-incubated with CLN at various times and used to treat SHSY-5Y neuroblastoma cells for up to 4 days. The cytotoxic effect was monitored by trypan blue exclusion. We demonstrated that 24-48 h treatment was the onset of toxicity of 10-50 microM of beta-amyloid peptides. Pre-incubation of 0.0025-0.25muM of CLN with 25 microM of beta-amyloid peptides leads to near-complete abolition of cytotoxicity. Low doses of CLN (2.5 nM) can attain cytotoxic protection levels similar to those of highest doses (0.25 microM). Thus, the time course for the appearance of beta-amyloid fibrils coincides with that for cytotoxicity, and that the reduction of fibrils of beta-amyloid peptides by CLN is concomitant with the reduction of the cytotoxic effects of beta-amyloid on SHSY-5Y neuroblastoma cells. Our studies suggest that the neuroprotective effects exerted by CLN are related to the reduction of beta-amyloid fibrils.

Alzheimer Disease↗
PubMed2004

Inhibition of amyloid A amyloidogenesis in vivo and in tissue culture by 4-deoxy analogues of peracetylated 2-acetamido-2-deoxy-alpha- and beta-d-glucose: implications for the treatment of various amyloidoses.

Two novel sugars, 2-acetamido-1,3,6-tri-O-acetyl-2,4-dideoxy-alpha- and beta-D-xylo-hexopyranoses, have been synthesized and their effects on heparan sulfate biosynthesis using primary mouse hepatocytes in tissue culture have been assessed. At concentrations of 0.1 and 1.0 mmol/L a mixture of both anomers significantly inhibited the biosynthesis of heparan sulfate by 60% and 99%, respectively. At 1.0 mmol/L the average molecular weight of the heparan sulfate synthesized is reduced from 77 kd to 40 kd. The biosynthetic inhibition is apparent within 1 hour (the earliest time point examined) of exposure of the hepatocytes to the analogues and appears virtually complete throughout a 24-hour incubation period. Using a radiolabeled version of the beta-anomer we demonstrate that the analogue is incorporated into growing heparan sulfate chains. The nature of the analogue, the quantity of analogue isotope incorporated, and the reduction in the size of the heparan sulfate polysaccharide are consistent with UDP activation and incorporation of the analogue and truncation of the growing heparan sulfate chain. At 0.1 mmol/L, and in the presence of a constant concentration of serum amyloid A (the precursor to AA amyloid), each analogue inhibited amyloid deposition (by 95 to 99%) in a tissue culture model of AA amyloidogenesis. At 6 mg/dose twice daily each analogue inhibited in vivo splenic AA amyloid deposition by 65 to 70% when using a rapid induction model of mouse AA amyloidogenesis. These data indicate that polysaccharides, such as heparan sulfate, play an integral part in the pathogenesis of AA amyloid deposition, and potentially other forms of amyloid. These data support our previous work that demonstrated that agents that mimic aspects of heparan sulfate structure and that interfere with heparan sulfate:amyloid protein binding inhibit AA amyloid deposition. They emphasize that heparan sulfate likely plays a critical role in amyloidogenesis, and compounds that interfere with heparan sulfate biosynthesis may provide leads for the development of anti-amyloid therapeutic agents.

Acetylation↗