Biomedical subjects

J P David

Publications and source records attributed to J P David.

At least 37 records · Page 2Linked to original sources

PubMed1999

The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease.

OBJECTIVE: To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD. BACKGROUND: The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment. METHODS: The study included 130 patients of various ages and different cognitive statuses, from nondemented control subjects (n = 60, prospective study) to patients with severe definite AD. Paired helical filaments (PHF)-tau and Abeta were used as biochemical and histologic markers of NFD and amyloid plaques, respectively. RESULTS: NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age >75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages according to the brain regions affected: transentorhinal cortex (S1), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal cortex (S5), medium temporal cortex (S6), polymodal association areas (prefrontal, parietal inferior, temporal superior) (S7), unimodal areas (S8), primary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10). Up to stage 6, the disease could be asymptomatic. In all cases studied here, stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired. CONCLUSIONS: The relationship between NFD and Alzheimer-type dementia, and the criteria for a biochemical diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.

Aged↗

PubMed1999

JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development.

BACKGROUND: The Jun N-terminal kinase (JNK) signaling pathway has been implicated in cell proliferation and apoptosis, but its function seems to depend on the cell type and inducing signal. In T cells, JNK has been implicated in both antigen-induced activation and apoptosis. RESULTS: We generated mice lacking the JNK2 isozymes. The mutant mice were healthy and fertile but defective in peripheral T-cell activation induced by antibody to the CD3 component of the T-cell receptor (TCR) complex - proliferation and production of interleukin-2 (IL-2), IL-4 and interferon-gamma (IFN-gamma) were reduced. The proliferation defect was restored by exogenous IL-2. B-cell activation was normal in the absence of JNK2. Activation-induced peripheral T-cell apoptosis was comparable between mutant and wild-type mice, but immature (CD4(+) CD8(+)) thymocytes lacking JNK2 were resistant to apoptosis induced by administration of anti-CD3 antibody in vivo. The lack of JNK2 also resulted in partial resistance of thymocytes to anti-CD3 antibody in vitro, but had little or no effect on apoptosis induced by anti-Fas antibody, dexamethasone or ultraviolet-C (UVC) radiation. CONCLUSIONS: JNK2 is essential for efficient activation of peripheral T cells but not B cells. Peripheral T-cell activation is probably required indirectly for induction of thymocyte apoptosis resulting from administration of anti-CD3 antibody in vivo. JNK2 functions in a cell-type-specific and stimulus-dependent manner, being required for apoptosis of immature thymocytes induced by anti-CD3 antibody but not for apoptosis induced by anti-Fas antibody, UVC or dexamethasone. JNK2 is not required for activation-induced cell death of mature T cells.

Animals↗

PubMed1999

Coping efforts in daily life: role of big five traits and problem appraisals.

The role of problem appraisal and Big Five traits in coping with bothersome daily events was investigated. Community-residing men completed diaries regarding stressful events and coping for eight consecutive days. Results of multi-level analyses indicated that lower perceived control over events was associated with greater reliance on distraction, catharsis, acceptance, seeking emotional social support, but less use of direct action. Stressor severity was positively associated with catharsis and religion, but negatively associated with acceptance. Neuroticism, Extraversion, Openness to experience, and Conscientiousness predicted coping strategy use. In addition, broad personality dimensions moderated relations between appraisals (perceived uncontrolability and severity) and coping strategy use. Although previous research implicated perceived control in coping, the present study suggests that both appraisals of stressor severity and individual differences in personality are also important determinants of coping strategy use at the daily level.

Adaptation, Psychological↗

PubMed1998

Loss of somatostatin-like immunoreactivity in the frontal cortex of Alzheimer patients carrying the apolipoprotein epsilon 4 allele.

We measured somatostatin-like immunoreactivity, using a radioimmunoassay which does not cross react with cortistatin-like immunoreactivity, in postmortem frontal cortex (Brodmann area 9) from 32 patients, of different apolipoprotein E genotypes, and presenting with different degrees of cognitive impairment. Eleven subjects and eight patients presented with no (controls) or limited memory impairments (Borderline), respectively. Six patients with clinical criteria for possible Alzheimer's disease also presented with clinical or brain imaging of cerebrovascular disease (mixed dementia) and seven patients were classified as Alzheimer's disease (AD). In the 6 months preceeding their deaths, all subjects had been evaluated by Folstein's Mini Mental State examination (MMS). Sixty nine percent of patients with MMS >20 did not carry the epsilon 4 allele while 66% of patients with MMS <10 did. Somatostatin concentrations (ng/mg wet weight) were significantly lower in the patients carrying the epsilon 4 allele (E2/3: 0.71 +/- 0.05, n = 19 vs. E4: 0.42 +/- 0.06, n = 13; mean +/- SEM, P < 0.001). These results, which are reminiscent of those obtained on cholinergic markers, suggest that apolipoprotein E4 is involved in the somatostatinergic dysfunction early after the onset in AD.

Aged↗

PubMed1998

The calcitonin receptor stimulates Shc tyrosine phosphorylation and Erk1/2 activation. Involvement of Gi, protein kinase C, and calcium.

While it is well established that adenylyl cyclase and phospholipase C-beta are two proximal signal effectors for the calcitonin receptor, the more distal signaling pathways are less well characterized. G protein-coupled receptors can activate Erk1/2 by Gs-, Gi-, or Gq-dependent signaling pathways, depending on the specific receptor and cell type examined. Since the calcitonin receptor can couple to all three of these G proteins, the ability of calcitonin to activate Erk1/2 was investigated. Calcitonin induced time- and concentration-dependent increases in Shc tyrosine phosphorylation, Shc-Grb2 association and Erk1/2 phosphorylation and activation in a HEK 293 cell line that stably expresses the rabbit calcitonin receptor C1a isoform. Pertussis toxin, which inactivates Gi, and calphostin C, a protein kinase C inhibitor, each partially inhibited calcitonin-induced Shc tyrosine phosphorylation, Shc-Grb2 association, and Erk1/2 phosphorylation. In contrast, neither forskolin nor H89, a protein kinase A inhibitor, had a significant effect on basal or calcitonin-stimulated Erk1/2 phosphorylation. Our results suggest that the calcitonin receptor induces Shc phosphorylation and Erk1/2 activation in HEK293 cells by parallel Gi- and PKC-dependent mechanisms. The calcitonin-induced elevation of cytosolic free Ca2+ was required for Erk1/2 phosphorylation, since preventing any change in cytosolic free Ca2+ by chelating both cytosolic and extracellular Ca2+ abolished the response. However, the change in Ca2+ that is induced by calcitonin is not sufficient to account for the calcitonin-induced Erk1/2 phosphorylation, since treatment with 100 nM ionomycin or 10 microM thapsigargin, each of which induced elevations of Ca2+ comparable to those induced by calcitonin, induced significantly less Erk1/2 phosphorylation than that induced by calcitonin. Erk1/2 may have important roles as downstream effectors mediating cellular responses to calcitonin stimulation.

Adaptor Proteins, Signal Transducing↗

PubMed1998

A new method to isolate large numbers of rabbit osteoclasts and osteoclast-like cells: application to the characterization of serum response element binding proteins during osteoclast differentiation.

We have developed a new method that allows the purification of large numbers of both authentic osteoclasts (OCs) and in vitro differentiated osteoclast-like cells (OCLs) from rabbits. We characterized the OCLs in terms of the expression of different phenotypic markers of OC differentiation and their ability to resorb bone. The method provides a system for performing biochemical and molecular studies of OC differentiation and function in a single species. We used this system to characterize the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the expression of proteins that bind to the serum response element (SRE) of the c-fos promoter. We found that OCLs and OCs displayed similar SRE-binding activities, including the serum response factor (SRF). This pattern is established in a time-dependent and cell-specific manner in response to long-term treatment of rabbit bone marrow by 1,25(OH)2D3. Thus, 1,25(OH)2D3 can modulate SRF and/or SRF-related protein. This finding may contribute to understanding the role of c-Fos in the regulation of OC differentiation.

Animals↗

PubMed1997

Glial reaction in the hippocampal formation is highly correlated with aging in human brain.

Glial fibrillary acidic protein (GFAP), a biochemical marker of astrocytes and glial reaction, was quantified by immunoblotting in different brain areas from 33 non-demented patients with a Mini Mental State Examination score above 26 and aged from 12 to 98 years. An increase of GFAP with age was first found in the hippocampus and then in the entorhinal cortex. In both regions, GFAP amounts were correlated with age (r = 0.768). In the isocortex, the increase of GFAP as a function of age was also significant (r = 0.672), but less than for the hippocampal region. GFAP levels increased dramatically after the age of 65 years, and more especially in the hippocampal formation. This glial reaction was observed in aged controls that do not show cognitive impairment and the neuropathological hallmarks of Alzheimer's disease.

Adolescent↗

PubMed1997

Different distribution of phosphorylated tau protein isoforms in Alzheimer's and Pick's diseases.

Tau proteins aggregate into different neuronal inclusions in several neurodegenerative disorders. In Alzheimer's disease (AD), hyperphosphorylated Tau from paired helical filaments (PHF) of neurofibrillary tangles, named PHF-Tau, have an electrophoretic profile with four main bands (Tau 55, 64, 69, 74 kDa). In Pick's disease, phosphorylated Tau from Pick bodies are made of two major components (Tau 55, 64 kDa) and a minor 69 kDa. Here we show, using specific antibodies against translated exon 2, 3 or 10 of Tau isoforms, that the set of Tau isoforms engaged in the most insoluble part of PHF in AD is made of Tau isoforms with exon 10 while they are lacking in phosphorylated Tau from Pick's disease. Our results suggest that specific sets of Tau isoforms distinguish between typical neuronal inclusions.

Alzheimer Disease↗

PubMed1997

c-Jun and cyclin D1 proteins as mediators of neuronal death after a focal ischaemic insult.

c-Jun, a transcriptional activator, as well as cyclin D1, a key regulator of the cell cycle, have been described in vitro as mediators of programmed neuronal death. After trophic factor deprivation, the activation of c-jun and cyclin D1 genes is considered as a necessary step within the cellular machinery that leads to cell death. We show here that both c-Jun and cyclin D1 proteins are present in neurones within the infarcted area after experimental cerebral ischaemia in the mouse. Since their presence was associated with DNA fragmentation revealed by the TUNEL procedure, we propose that c-Jun and cyclin D1 are involved in the process of neuronal death.

Animals↗

PubMed1997

Why listeners hear less than they are told: attentional load and the teller-listener extremity effect.

Prior research (T. Gilovich, 1987; M. Inman, A. Reichl, & R. Baron, 1993) indicated that individuals (tellers) who directly observe an actor (on video tape) rate that actor less extremely than other individuals (listeners) who hear the tellers' secondhand accounts of the actor's actions. Evidence has suggested that this teller-listener effect is due at least in part to listeners' failure to encode and consider mitigating circumstances contributing to the actors' actions (Inman et al., 1993). The present research examined several explanations for this phenomenon. Study 1 found stronger teller-listener differences (and less recall of mitigating information) when listeners heard the teller's account in the presence of noise. Studies 2 and 3 found listener's interpretations to be more extreme when the verbal accounts they heard were verbally disorganized. These results support an attentional load explanation for teller-listener differences.

Attention↗

PubMed1997

Differential roles of neuroticism, extraversion, and event desirability for mood in daily life: an integrative model of top-down and bottom-up influences.

Top-down and bottom-up approaches were combined to assess the relative impact of extraversion, neuroticism, and daily events on daily mood. Ninety-six community-residing men completed diaries for 8 consecutive nights. Extraversion predicted positive mood, whereas neuroticism predicted positive and negative mood. Undesirable events predicted negative mood and, more modestly, positive mood. Desirable events predicted positive mood. Negative dispositional and situational factors play a larger role in daily positive affect than positive factors do in daily negative affect.

Adult↗

PubMed1997

Two-dimensional characterization of paired helical filament-tau from Alzheimer's disease: demonstration of an additional 74-kDa component and age-related biochemical modifications.

PHF-tau proteins are the major components of the paired helical filament (PHF) from Alzheimer's disease (AD) neurofibrillary lesions. They differ both qualitatively and quantitatively in their degree of phosphorylation when compared with native tau proteins. However, little is known about the extent and heterogeneity of phosphorylated sites or the isoform composition and the isoelectric variants of PHF-tau. Therefore, we have characterized PHF-tau proteins from cortical brain tissue homogenates of 13 AD patients using two-dimensional gel electrophoresis. Whatever the topographical origin of brain tissue homogenates, PHF-tau proteins shared the same two-dimensional gel electrophoresis profile made of a tau triplet of 55, 64, and 69 kDa. A 74-kDa hyperphosphorylated tau component was detected particularly in the youngest and most severely affected AD patients. This additional component of hyperphosphorylated tau was shown to correspond to the longest brain tau isoform. Furthermore, the isoelectric points of PHF-tau from older AD patients were significantly more basic, indicating a lower degree of phosphorylation. These results show that the severity of neurofibrillary degeneration of AD is modulated by age.

Aged↗

PubMed1996

Personality and coping: three generations of research.

This article introduces the Journal of Personality's special issue on coping and personality. It first presents a historical overview of the psychological study of how people cope with stress and identifies three generations of theory and research: (a) the psychoanalysts and the ego development school, which tended to equate personality and coping strategies; (b) the transactional approach, which appeared in the 1960s and emphasized situational and cognitive influences on coping while downplaying the role of individual differences; and (c) the most recent, "third generation," whose work is represented in this special issue and focuses on the role of personality in coping while maintaining strong operational distinctions among coping, personality, appraisal, and adaptational outcomes. This introduction concludes with a discussion of unresolved conceptual and methodological issues and a brief orientation to the third-generation articles that follow in this special issue.

Adaptation, Psychological↗

PubMed1996

Coping and personality: third time's the charm?

In this special issue, a third generation of research is represented which recognizes and demonstrates that individual differences in personality play an important role in the coping process. Although progress is apparent, there are several unresolved issues, including the best way to measure coping and whether "type of coping" matters in naturalistic settings. Three potentially important parameters of coping-range, patterning, and competence-are described, but only the first has received systematic empirical attention. The study of coping might also be advanced by researchers giving more attention to the differences between problem situations in which traits are more easily expressed ("weak" situations) versus those where normative criteria and constraints are explicit ("strong" situations).

Adaptation, Psychological↗

PubMed1995

Quantitation of Alzheimer's amyloid peptide and identification of related amyloid proteins by dot-blot immunoassay.

In Alzheimer's disease, the main component of amyloid deposits is a 39-43 amino acid peptide referred to as amyloid peptide or A beta. A crucial issue in the study of this disorder is to define the sequence of events that lead to amyloid deposition. In the present study, a new approach was developed that allows to specifically solubilize A beta peptide trapped within amyloid deposits and to quantify its amount by dot-blot immunoassay. The present method also permits to isolate components tightly bound to A beta and that are likely to catalyze its aggregation. Biochemical A beta quantitation was performed in 4 Brodmann areas from 17 elderly individuals exhibiting different degrees of amyloidosis. In parallel, classical neuropathology was done by histochemical and immunohistochemical methods. A beta amounts (pmol) were correlated to the number of amyloid deposits determined by neuropathology showing high statistical significance. Moreover, amyloid-binding proteins including apolipoprotein E and heparan sulfate proteoglycans were also found associated to A beta in the amyloid preparation. The present biochemical procedure is a new and reliable method to quantify amyloid deposition in brain. Furthermore, it allows to detect amyloid-associated components such as apolipoprotein E, that may be involved in the pathological process of amyloidogenesis.

Aged↗

PubMed1995

Cortical mapping of Alzheimer pathology in brains of aged non-demented subjects.

1. The presence of Alzheimer-type neurofibrillary pathology and amyloid deposits within the brains of 27 aged non-demented subjects was investigated by immunoblotting and immunohistochemistry using antibodies directed against pathological Tau proteins 55, 64 and 69 and beta A4 respectively. 2. The abnormal Tau triplet, a biochemical marker of neurofibrillary degeneration was quantified by western blot and densitometric analysis in several cortical areas including the entorhinal cortex (EC), hippocampus and Brodmann areas (BA) 38, 20, 22, 35, 9, 44 and 39. 3. The abnormal Tau triplet was detected in the EC and the hippocampus of most of the controls aged over 70 years. In few control cases abnormal Tau proteins were also detected in the isocortex, in BA38 alone or also in BA20. Some cases and especially those with Tau pathology in the temporal lobe contained numerous senile plaques (SP) in the neocortex. 4. The authors conclude that control cases with Tau pathology in the temporal lobe and numerous SP in the neocortex were likely to be subclinical stages of AD whereas others with Tau pathology exclusively detected in the EC and hippocampus and without or few SP in the neocortex were related to normal aging.

Aged↗

PubMed1994

[Normal cerebral aging: study of glial reaction].

Glial fibrillary acidic protein (GFAP), a biochemical marker of astrocytes and glial reaction, was quantified in different brain areas from 16 non-demented patients with a mini mental state score > 25/30 and aged from 21 to 95 years. For each brain, we analyzed the hippocampus (H), the parahippocampus gyrus (GPH) and the neocortical Brodmann areas 9, 22, 39, 44. The quantification of GFAP was performed on the different brain homogenates treated with SDS, using a Western blot method and an immunodetection with a monoclonal antibody against human GFAP. The quantity of GFAP found in the hippocampus and the parahippocampal region were significantly increased as a function of age (p < 0.001). This was not observed for neocortical areas. It has been shown that hippocampal and parahippocampal regions are specifically affected by the Alzheimer-type degenerating process during aging. Glial reaction, as visualized by immunoblotting, could be directly linked to this phenomenon.

Adult↗

PubMed1992

Presence of abnormally phosphorylated Tau proteins in the entorhinal cortex of aged non-demented subjects.

An immunoblot study was performed in several cortical samples from non-demented aged controls and compared with those from Alzheimer patients, using antibodies against Tau 55, 64 and 69, which are specific and reliable markers of the neurofibrillary degeneration of the Alzheimer type. The immunodetection of Tau 55, 64 and 69 was positive in all cortical areas from Alzheimer patients, in the entorhinal cortex from each control aged more than 65 but not in cortical samples from younger controls. We demonstrate that the entorhinal cortex is the most vulnerable neuronal population in aging and that the biochemical dysfunctions observed in this area are typically of the 'Alzheimer-type'.

Aged↗