PubMed Health⌕ Search

Biomedical subjects

M Tabaton

Publications and source records attributed to M Tabaton.

At least 37 records · Page 2Linked to original sources
PubMed2000

Generation of an apoptotic intracellular peptide by gamma-secretase cleavage of Alzheimer's amyloid beta protein precursor.

The amyloid beta protein precursor (AbetaPP) is sequentially processed by beta- and gamma-secretases to generate the Abeta peptide. The biochemical path leading to Abeta formation has been extensively studied since extracellular aggregates of amyloidogenic forms of Abeta peptide (Abeta42) are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of AbetaPP proteolysis is unknown. Although never previously described, cleavage of AbetaPP by gamma-secretase should release, together with Abeta, a COOH-terminal AbetaPP Intracellular Domain, herein termed AID. We have now identified AID-like peptides in brain tissue of normal control and patients with sporadic Alzheimer's disease and demonstrate that AID acts as a positive regulator of apoptosis. Thus, overproduction of AID may add to the toxic effect of Abeta42 aggregates and further accelerate neurodegeneration.

Journal Article↗
PubMed1999

Tyrosine kinase A-nerve growth factor receptor is antigenically present in dystrophic neurites from a variety of conditions but not in Alzheimer's disease.

Tyrosine kinase A (TrkA), a high affinity receptor for nerve growth factor (NGF), is activated during differentiation and regeneration of selective neuronal population. We investigated presence, distribution and expression of TrkA in frontal cortex from cases with Alzheimer's disease (AD), normal aging and a variety of conditions (AIDS, cystic fibrosis, cerebral infarcts) in which neuroaxonal dystrophy occurs. TrkA was immunocytochemically detected in 90% of dystrophic neurites surrounding amyloid deposits in normal aging, as well as in all not amyloid-related dystrophic neurites identified by ubiquitin immunoreactivity. Conversely, the amyloid associated dystrophic neurites were not TrkA reactive in AD tissue. The levels of TrkA protein and mRNA in AD frontal cortex did not significantly differ from those of non-demented aged controls. The absence of TrkA activation in amyloid associated neurites in AD, but not in normal aging, indicates a different reaction of neuronal tissue to amyloid (protein (Abeta) deposition, and suggests that other factors, besides Abeta, mediate neuronal degeneration in AD.

AIDS Dementia Complex↗
PubMed1999

Alternative, non-secretase processing of Alzheimer's beta-amyloid precursor protein during apoptosis by caspase-6 and -8.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Although the pathogenesis of AD is unknown, it is widely accepted that AD is caused by extracellular accumulation of a neurotoxic peptide, known as Abeta. Mutations in the beta-amyloid precursor protein (APP), from which Abeta arises by proteolysis, are associated with some forms of familial AD (FAD) and result in increased Abeta production. Two other FAD genes, presenilin-1 and -2, have also been shown to regulate Abeta production; however, studies examining the biological role of these FAD genes suggest an alternative theory for the pathogenesis of AD. In fact, all three genes have been shown to regulate programmed cell death, hinting at the possibility that dysregulation of apoptosis plays a primary role in causing neuronal loss in AD. In an attempt to reconcile these two hypotheses, we investigated APP processing during apoptosis and found that APP is processed by the cell death proteases caspase-6 and -8. APP is cleaved by caspases in the intracellular portion of the protein, in a site distinct from those processed by secretases. Moreover, it represents a general effect of apoptosis, because it occurs during cell death induced by several stimuli both in T cells and in neuronal cells.

Alzheimer Disease↗
PubMed1999

Tau gene mutation in familial progressive subcortical gliosis.

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22. This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias. Some of these kindreds have mutations in the tau gene. We report here that PSG-1 has a tau mutation at position +16 of the intron after exon 10. The mutation destabilizes a predicted stem-loop structure and leads to an over-representation of the soluble four-repeat tau isoforms, which assemble into wide, twisted, ribbon-like filaments and ultimately result in abundant neuronal and glial tau pathology. The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau. The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.

Cerebral Cortex↗
PubMed1999

Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau.

The tau gene has been found to be the locus of dementia with rigidity linked to chromosome 17. Exonic and intronic mutations have been described in a number of families. Here we describe a P301S mutation in exon 10 of the tau gene in a new family. Two members of this family were affected. One individual presented with frontotemporal dementia, whereas his son has corticobasal degeneration, demonstrating that the same primary gene defect in tau can lead to 2 distinct clinical phenotypes. Both individuals developed rapidly progressive disease in the third decade. Neuropathologically, the father presented with an extensive filamentous pathology made of hyperphosphorylated tau protein. Biochemically, recombinant tau protein with the P301S mutation showed a greatly reduced ability to promote microtubule assembly.

Adult↗
PubMed1998

Opposite roles of apolipoprotein E in normal brains and in Alzheimer's disease.

We have characterized the interaction between apolipoprotein E (apoE) and amyloid beta peptide (Abeta) in the soluble fraction of the cerebral cortex of Alzheimer's disease (AD) and control subjects. Western blot analysis with specific antibodies identified in both groups a complex composed of the full-length apoE and Abeta peptides ending at residues 40 and 42. The apoE-Abeta soluble aggregate is less stable in AD brains than in controls, when treated with the anionic detergent SDS. The complex is present in significantly higher quantity in control than in AD brains, whereas in the insoluble fraction an inverse correlation has previously been reported. Moreover, in the AD subjects the Abeta bound to apoE is more sensitive to protease digestion than is the unbound Abeta. Taken together, our results indicate that in normal brains apoE efficiently binds and sequesters Abeta, preventing its aggregation. In AD, the impaired apoE-Abeta binding leads to the critical accumulation of Abeta, facilitating plaque formation.

Alzheimer Disease↗
PubMed1998

Early glycoxidation damage in brains from Down's syndrome.

In Down's syndrome, the presence of three copies of chromosome 21 is associated with premature aging and progressive mental retardation sharing the pathological features of Alzheimer disease. Early cortical dysgenesis and late neuronal degeneration are probably caused by an overproduction of amyloid beta-peptide, followed by an increased cellular oxidation. Interestingly, chromosome 21 codes for superoxide-dismutase and amyloid beta precursor resulting, in Down's syndrome, in an overflow of these gene products and metabolites. We studied Down's fetal brain cortex to evaluate the presence and amount of lipid and protein oxidation markers; moreover, we quantified two forms of glycation end products that are known to be involved in the process of cellular oxidation. All these parameters are significantly increased in Down's fetal brains in comparison to controls, providing the evidence that accelerated brain glycoxidation occurs very early in the life of Down's syndrome subjects.

Aldehydes↗
PubMed1998

Increased amyloidogenic secretion in cerebellar granule cells undergoing apoptosis.

Some clues suggest that neuronal damage induces a secondary change of amyloid beta protein (Abeta) metabolism. We investigated this possibility by analyzing the secretion of Abeta and processing of its precursor protein (amyloid precursor protein, APP) in an in vitro model of neuronal apoptosis. Primary cultures of rat cerebellar granule neurons were metabolically labeled with [35S]methionine. Apoptosis was induced by shifting extracellular KCl concentration from 25 mM to 5 mM for 6 h. Control and apoptotic neurons were then subjected to depolarization-stimulated secretion. Constitutive and stimulated secretion media and cell lysates were immunoprecipitated with antibodies recognizing regions of Abeta, full-length APP, alpha- and beta-APP secreted forms. Immunoprecipitated proteins were separated by SDS/PAGE and quantitated with a PhosphorImager densitometer. Although intracellular full-length APP was not significantly changed after apoptosis, the monomeric and oligomeric forms of 4-kDa Abeta were 3-fold higher in depolarization-stimulated secretion compared with control neurons. Such increments were paralleled by a corresponding increase of the beta-APPs/alpha-APPs ratio in apoptotic secretion. Immunofluorescence studies performed with an antibody recognizing an epitope located in the Abeta sequence showed that the Abeta signal observed in the cytoplasm and in the Golgi apparatus of control neurons is uniformly redistributed in the condensed cytoplasm of apoptotic cells. These studies indicate that neuronal apoptosis is associated with a significant increase of metabolic products derived from beta-secretase cleavage and suggest that an overproduction of Abeta may be the consequence of neuronal damage from various causes.

Amyloid beta-Peptides↗
PubMed1998

Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress.

Increased awareness for a role of oxidative stress in the pathogenesis of Alzheimer's disease has highlighted the issue of whether oxidative damage is a fundamental step in the pathogenesis or instead results from disease-associated pathology. In vitro experiments support both possibilities: Oxidative stress increases amyloid-beta production, and, conversely, amyloid-beta increases oxidative damage. To address the relationship between amyloid-beta and oxidative stress in vivo, we examined, using an array of oxidative markers, transgenic mice that overexpress amyloid-beta precursor protein and, as in Alzheimer's disease, develop characteristic amyloid-beta deposits within the brain parenchyma. Transgenic animals show the same type of oxidative damage that is found in Alzheimer's disease, and it is important that this damage directly correlates with the presence of amyloid-beta deposits. The significance of these studies is twofold. First, they provide evidence that amyloid-beta and oxidative damage are inextricably linked in vivo. Second, they support the use of transgenic animals for the development of antioxidant therapeutic strategies.

Aldehydes↗
PubMed1997

Heterogeneity of water-soluble amyloid beta-peptide in Alzheimer's disease and Down's syndrome brains.

Water-soluble amyloid beta-peptides (sA beta), ending at residue 42, precede amyloid plaques in Down's syndrome (DS). Here we report that sA beta consists of the full-length A beta(1-42) and peptides truncated and modified by cyclization of the N-terminal glutamates, A beta[3(pE)-42] and A beta[11(pE)-42]. The A beta[3(pE)-42] peptide is the most abundant form of sA beta in Alzheimer's disease (AD) brains. In DS, sA beta[3(pE)-42] concentration increases with age and the peptide becomes a dominant species in the presence of plaques. Both pyroglutamate-modified peptides and the full-length A beta form a stable aggregate that is water soluble. The findings point to a crucial role of the aggregated and modified sA beta in the plaque formation and pathogenesis of AD.

Alzheimer Disease↗
PubMed1997

Is amyloid beta-protein glycated in Alzheimer's disease?

Recent data suggest that protein glycation is involved in the process of amyloid formation in Alzheimer's disease (AD). To further investigate this issue, we analyzed the presence of advanced glycation end products (AGE) in soluble and insoluble forms of amyloid beta-protein (A beta) as well as in apolipoprotein E (apoE), a protein bound to amyloid deposits. Both proteins were extracted from cerebral cortex obtained from patients with AD and probed by immunoblotting with two antibodies specific for different AGE, already known to immunocytochemically label amyloid plaques. All the AGE antibodies failed to recognize either A beta or apoE, whereas they reacted with synthetic A beta glycated in vitro. These findings indicate that other proteins associated with amyloid deposits are candidates to be modified with AGE in Alzheimer's cerebral tissue.

Alzheimer Disease↗
PubMed1996

Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down's syndrome.

Abnormal and excessive accumulation of the amyloid beta-peptide (A beta) in the brain is a major and common characteristic of all Alzheimer's disease (AD) forms irrespective of their genetic background. Insoluble aggregates of A beta are identified as amyloid plaques. These deposits are thought to form when the amount of A beta is increased in the brain parenchyma as a result of either overexpression or altered processing of the amyloid precursor protein (APP). Soluble A beta ending at carboxyl-terminal residue 40 (A beta 40) and, in lesser amount, the form ending at residue 42 (A beta 42), are normal products of the APP metabolism in cell cultures. Increased secretion of soluble A beta 42 has been observed in cells transfected with constructs modeling APP gene mutations of familial forms of AD (refs 4, 5). On the basis of these in vitro data it has been hypothesized that the presence of soluble A beta 42 plays a role in the formation of amyloid plaques. Subjects affected by Down's syndrome (DS) have an increased APP gene dosage and overexpress APP. Apparently because of this overexpression, they almost invariably develop amyloid deposits after the age of 30 years, although they are free of them at earlier ages. Moreover, it has been observed that A beta 42 precedes A beta 40 in the course of amyloid deposition in DS brain. Thus, DS subjects provide the opportunity to investigate in the human brain the metabolic conditions that precede the formation of the amyloid deposits. Here we report that soluble A beta 42 is present in the brains of DS-affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age-matched controls. It is argued that overexpression of APP leads specifically to A beta 42 increase and that the presence of the soluble A beta 42 is causally related to plaque formation in DS and, likely, in AD brains.

Adolescent↗
PubMed1996

What can artificial neural networks teach us about neurodegenerative disorders with extrapyramidal features?

Artificial neural networks (ANNs), computer paradigms that can learn, excel in pattern recognition tasks such as disease diagnosis. Artificial neural networks operate in two different learning modes: supervised, in which a known diagnostic outcome is presented to the ANN, and unsupervised, in which the diagnostic outcome is not presented. A supervised learning ANN could emulate human expert diagnostic performance and identify relevant predictive markers in the diagnostic task, while an unsupervised learning ANN could suggest reasonable alternative diagnostic classification criteria. In the present study, we used ANN methodology to try to overcome the neuropathological difficulties in differentiating the subtypes of progressive supranuclear palsy (PSP), and in differentiating PSP from postencephalitic parkinsonism (PEP) and corticobasal degeneration, or Pick's disease from corticobasal degeneration. First, we applied supervised learning ANN to classify 62 cases of these disorders and to identify diagnostic markers that distinguish them. In a second experiment, we used unsupervised learning ANN to investigate possible alternative nosological classifications. Artificial neural networks input data for each case consisted of values representing histological features, including neurofibrillary tangles, neuronal loss and gliosis found in multiple brain sampling areas. The supervised learning ANN achieved excellent accuracy in classifying PSP but had difficulty classifying the other disorders. This method identified a few features that might help to differentiate PEP, supported currently proposed criteria for Pick's disease, corticobasal degeneration and typical PSP, but detected no features to characterize the atypical subtype of PSP. In general, unsupervised learning ANN supported the present nosological classification for PSP, PEP, Pick's disease and corticobasal degeneration, although it overlapped some groups. Artificial neural networks methodology appears promising for studying neurodegenerative disorders.

Basal Ganglia Diseases↗
PubMed1996

Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders.

We investigated the validity and reliability of diagnoses made by eight neuropathologists who used the preliminary NINDS neuropathologic diagnostic criteria for progressive supranuclear palsy (PSP) and related disorders. The specific disorders were typical, atypical, and combined PSP, postencephalitic parkinsonism, corticobasal ganglionic degeneration, and Pick's disease. These disorders were chosen because of the difficulties in their neuropathologic differentiation. We assessed validity by measuring sensitivity and positive predictive value. Reliability was evaluated by measuring pairwise and group agreement. From a total of 62 histologic cases, each neuropathologist independently classified 16 to 19 cases for the pairwise analysis and 5 to 6 cases for the group analysis. The neuropathologists were unaware of the study design, unfamiliar with the assigned cases, and initially had no clinical information about the cases. Our results showed that with routine sampling and staining methods, neuropathologic examination alone was not fully adequate for differentiating the disorders. The main difficulties were discriminating the subtypes of PSP and separating postencephalitic parkinsonism from PSP. Corticobasal ganglionic degeneration and Pick's disease were less difficult to distinguish from PSP. The addition of minimal clinical information contributed to the accuracy of the diagnosis. On the basis of results obtained, we propose clinicopathologic diagnostic criteria to improve on the NINDS criteria.

Aged↗
PubMed1995

Familial progressive subcortical gliosis: presence of prions and linkage to chromosome 17.

Progressive subcortical gliosis (PSG) is a sporadic and familial dementing disease characterized pathologically by astrogliosis at the cortex-white matter junction, a feature present in some prion diseases. With immunocytochemical and Western blot analyses, we investigated the presence of deposits of the prion protein (PrP) and of the protease-resistant PrP isoform, the hallmarks of prion diseases, in six affected members of two large kindreds with PSG. The coding region of the PrP gene was sequenced and chromosomal linkage determined. We demonstrated "diffuse" PrP plaques in the cerebral cortex of two subjects from one kindred and protease-resistant PrP fragments in four of the five subjects examined. We found no mutation in the coding region of the PrP gene. Moreover, the disease was linked to chromosome 17 and not to chromosome 20, where the PrP gene resides. The familial form of PSG is the first human genetic disease characterized by the presence of protease-resistant PrP that lacks a mutation in the coding region of the PrP gene. The linkage to chromosome 17 suggests that other genes are involved in the PrP metabolism. Whether the protease-resistant PrP plays a primary or secondary role in the pathogenesis of this form of PSG remains to be determined.

Adult↗
PubMed1995

Apolipoprotein E epsilon 4 allele frequency is not increased in progressive supranuclear palsy.

We examined apolipoprotein E (ApoE) immunoreactivity and allele frequency in 12 autopsied cases of progressive supranuclear palsy (PSP), a neurodegenerative disease characterized by diffuse neurofibrillary tangle (NFT) formation without beta-amyloid deposits. In spite of the ApoE immunoreactivity associated with NFTs, in PSP the ApoE allele frequency was comparable with that of age-matched normal controls. This suggests that in Alzheimer's disease the increased frequency of ApoE epsilon 4 does not influence neurofibrillary degeneration, but is probably linked to beta-amyloid deposition.

Alleles↗
PubMed1994

Soluble amyloid beta-protein is a marker of Alzheimer amyloid in brain but not in cerebrospinal fluid.

The amyloid beta protein (A beta), a 4 kD fragment of the beta amyloid precursor protein, is deposited as insoluble amyloid in the brain of Alzheimer disease (AD) subjects. Soluble A beta is a normal metabolic product and is present in cerebrospinal fluid. We identified soluble A beta forms of 4kD, 3kD and 3.7kD in AD but not in control brains free of amyloid deposits. All three forms of soluble A beta extend beyond residue 40. Analysis of cerebrospinal fluid from the same subjects confirmed the presence of only 4kD A beta in comparable amounts in AD and controls. The presence of soluble A beta only in brain regions with amyloid suggests they are related. The undetectability of soluble A beta in control brains indicates that it is normally removed or bound to other proteins. Failure of this protective mechanism might cause amyloid formation in AD.

Alzheimer Disease↗