Inflammatory markers and adipokines alter adipocyte-derived ASP production through direct and indirect immune interaction.

Obesity and related metabolic diseases are associated with chronic low-grade inflammation, characterized by increased pro-inflammatory proteins. Several studies have demonstrated increases in acylation stimulating protein (ASP) and its precursor protein C3 in obesity, diabetes and dyslipidemia. To evaluate the effects of acute inflammatory factors and adipokines on ASP production and potential mechanisms of action, 3T3-L1 adipocytes were treated for 24 h with adipokines, cytokines, macrophage-conditioned media and direct co-culture with J774 macrophages. ASP and C3 in the media were evaluated in relation to changes in adipocyte lipid metabolism (cellular triglyceride stores). Leptin, adiponectin, IL-10, LPS and TNF-α increased ASP production (151%, 153%, 190%, 318%, 134%, P<0.05, respectively,). C5a and RANTES (Regulated and normal T cell expressed and secreted) decreased ASP production ( - 34%, - 47%, P<0.05), which was also associated with a decrease in the precursor protein C3 ( - 39% to - 51%, P<0.01), while keratinocyte chemoattractant (KC; murine IL-8 ortholog) had no effect on ASP and C3 secretion. By contrast, apelin, omentin and visfatin also decreased ASP ( - 27%, - 49%, - 22%, P<0.05), but without changes in precursor protein C3 secretion. Macrophage-conditioned media alone had little effect on C3 or ASP, while co-culture of adipocytes with macrophages markedly increased ASP and C3 production (272%, 167%, P<0.05). These in vitro results suggest various metabolic hormones and inflammatory factors can affect ASP production through increased precursor C3 production and/or by changing the rate of C3 conversion to ASP. As an adipokine, ASP could constitute a new link between adipocytes and macrophages.

[Novel adipokines: links between obesity and atherosclerosis]. / Récentes adipokines : un lien entre l'obésité et l'athérosclérose.

Today, cardiovascular diseases (CVD) remain the principal cause of death in industrialized countries and are linked to obesity and metabolic syndrome. Metabolic syndrome is characterized by changes in arterial blood pressure, glucose metabolism, lipid and lipoprotein profiles in addition to inflammation. Adipose tissue produces many cytokines and secretory factors termed adipokines. Intra-abdominal (visceral) adipose tissue in particular, rather than peripheral, appears to be associated with global cardiometabolic risk. The present article summarizes information on five recently discovered adipokines: vaspin, visfatin, apelin, acylation stimulating protein (ASP) and retinol-binding protein 4 (RBP4) and their potential beneficial or deleterious roles in obesity and atherosclerosis. Vaspin may have antiatherogenic effects through its potential insulin-sensitizing properties. Similarly, visfatin has been suggested to enhance insulin sensitivity, but its potential role in plaque destabilization may counteract this. Apelin, via inhibition of food intake, and increases in physical activity and body temperature, may promote weight loss, resulting in a beneficial antiatherogenic effect. Further, favourable effects on vasodilatation and blood pressure add to this positive effect. Considering its increased levels in subjects with demonstrated atherosclerosis, RBP4 may constitute a biomarker. Lastly, ASP, often increased in obesity and metabolic disorders, may be contributing to efficient lipid storage, and decreasing or blocking ASP may provide a potential antiobesity target. Adipokines may further contribute to obesity-atherosclerosis relationships, the full understanding of which will require further research.

Expression of prostaglandin E synthases in the bovine oviduct.

The oviduct is a specialized organ responsible for the storage and the transport of male and female gametes. It also provides an optimal environment for final gamete maturation, fertilization, and early embryo development. Prostaglandin (PG) E(2) is involved in many female reproductive functions, including ovulation, fertilization, implantation, and parturition. However, the control of its synthesis in the oviduct is not fully understood. Cyclooxygenases (COXs) are involved in the first step of the transformation of arachidonic acid to PGH(2.) The prostaglandin E synthases (PGESs) constitute a family of enzymes that catalyze the conversion of PGH(2) to PGE(2), the terminal step in the formation of this bioactive prostaglandin. Quantitative real-time PCR was used to determine the expression of COX-1, COX-2, microsomal prostaglandin E synthase-1 (mPGES-1), microsomal prostaglandin E synthase-2 (mPGES-2), and cytosolic prostaglandin E synthase (cPGES) mRNA in various sections of the oviduct, both ipsilateral and contralateral (to the ovary on which ovulation occurred) at various stages of the estrous cycle. Furthermore, protein expression and localization of cPGES, mPGES-1, and mPGES-2 were determined by Western blot and immunohistochemistry. All three PGESs were detected at both mRNA and protein levels in the oviduct. These PGESs were mostly concentrated in the oviductal epithelial layer and primarily expressed in the ampulla section of the oviduct and to a lesser extent in the isthmus and the isthmic-ampullary junction. The mPGES-1 protein was highly expressed in the contralateral oviduct, which contrasted with mPGES-2 mostly expressed in the ipsilateral oviduct. This is apparently the first report documenting that the three PGESs involved in PGE(2) production were present in the Bos taurus oviduct.

Expression of superoxide dismutases in the bovine oviduct during the estrous cycle.

The superoxide dismutases (SODs) are first-line enzymatic antioxidants that dismute superoxide anion (O(2)(-)*) to produce hydrogen peroxide (H(2)O(2)). The primary objective was to characterize, by western blot analysis, the expression of two SODs, the cytosolic (Cu,ZnSOD or SOD1) and the mitochondrial (MnSOD or SOD2) forms in three sections of the oviduct, i.e. isthmus (I), ishtmic-ampullary junction (IA), and ampulla (A), during the estrous cycle. The Cu,ZnSOD and MnSOD proteins were mostly expressed in the ampulla (I

Environmental pesticide exposure as a risk factor for Alzheimer's disease: a case-control study.

The aim of this study was to evaluate the influence of pesticide exposure on the development of Alzheimer's disease (AD), taking into account the potentially confounding factors (genetic, occupational exposure, and sociodemographic). The 1924 study participants (>70 years old) were randomly selected in the Saguenay-Lac Saint-Jean region (Quebec, Canada). The AD diagnosis was established in three steps according to recognized criteria. Sixty-eight cases were paired with a nondemented control for age (+/-2 years) and sex. Structured questionnaires addressed to subjects and proxy respondents allowed a description of the sociodemographic characteristics, lifestyle characteristics, and residential, occupational, familial, and medical histories. Assessment of environmental exposure to pesticides was based on residential histories and the agriculture census histories of Statistics Canada (1971-1991) for herbicide and insecticide spraying in the area. Statistical analyses were performed with a logistic regression, adjusting for potential confounding factors. The results failed to show a significant risk of AD with an exposure to herbicides, insecticides, and pesticides. However, future investigations are needed to establish more precisely the identification, measurement, mobility, and bioavailability of neurotoxic pesticide residues in relation to AD.

Aluminum forms in drinking water and risk of Alzheimer's disease.

The objective of this study was to assess the relation between long-term exposure to different aluminum (Al) forms in drinking water and Alzheimer's disease (AD). The study participants were selected from a random sample of the elderly population (> or = 70 years of age) of the Saguenay-Lac-Saint-Jean region (Quebec). Sixty-eight cases of Alzheimer's disease diagnosed according to recognized criteria were paired for age (+/-2 years) and sex with nondemented controls. Aluminum speciation was assessed using established standard analytical protocols along with quality control procedures. Exposure to Al forms (total Al, total dissolved Al, monomeric organic Al, monomeric inorganic Al, polymeric Al, Al(3+), AlOH, AlF, AlH(3)SiO(2+)(4), AlSO(4)) in drinking water was estimated by juxtaposing the subject's residential history with the physicochemical data of the municipalities. The markers of long-term exposures (1945 to onset) to Al forms in drinking water were not significantly associated with AD. On the other hand, after adjustment for education level, presence of family cases, and ApoE varepsilon4 allele, exposure to organic monomeric aluminum estimated at the onset of the disease was associated with AD (odds ratio 2.67; 95% CI 1.04-6.90). On average, the exposure estimated at the onset had been stable for 44 years. Our results confirm prime the importance of estimation of Al speciation and consideration of genetic characteristics in the assessment of the association between aluminum exposure and Alzheimer's disease.

Phylogenetic analysis of the mitochondrial genome indicates significant differences between patients with Alzheimer disease and controls in a French-Canadian founder population.

The activity of cytochrome oxidase (CO), the terminal enzyme of the mitochondrial electron transport chain, has been reported to be lower in the brains of Alzheimer disease (AD) patients. This suggests that a modification of mitochondrial DNA (mtDNA) may be responsible for this decrease of CO activity. Many mtDNA variants were found by different studies at a higher frequency in AD patients, suggesting that mtDNA variants could confer a genetic susceptibility to AD. In this study, we sequenced the entire mitochondrial genome region that encompasses the three CO genes and the 22 mitochondrial tRNA in 69 AD patients and 83 age-matched controls. We detected a total of 95 mtDNA variants. The allele frequencies of the majority of these variants were similar in patients and controls. However, a haplotype composed of three different modifications (positions: 5633, 7476, and 15812) was present in three of the 69 late-onset AD patients (4.3%) and also in 1 of 16 early-onset AD patients (6.2%) but not in control individuals. Given that one of these variants (15812) has already been shown to be associated with another neurodegenerative disease and that all three modifications are relatively conserved and their frequencies in the general population is only 0.1%, our data suggest that the presence of this haplotype may represent a risk factor for AD. We also found a significant association (P < 0.05) of two other variants at positions 709 (rRNA 12S) and 15928 (tRNA(Thr)). These two mtDNA variants are three times more frequent in control individuals compared with AD patients, suggesting that they may be protective against AD.

A genealogical study of Alzheimer disease in the Saguenay region of Quebec.

We performed an analysis of inbreeding and kinship among the ascending genealogies of 205 autopsy-confirmed Alzheimer disease (AD) subjects recruited in the Saguenay area of Québec. We hypothesized that if some traits pertaining to the disease were determined by inherited factors, and if the corresponding genes were not too frequent in the population, it might be possible to detect some clusters of patients related to common ancestors and presenting a level of kinship and/or inbreeding higher than is observed in the unaffected population of the same age. In view of the heterogeneity of the disease, we also verified if some of the factors investigated could be associated more specifically with subsets of cases based on age of onset and on apolipoprotein E (APOE) genotype. Results were compared with those obtained on 205 controls matched for gender, place and year of birth. We found that late-onset AD cases with an APOE-epsilon 4 were significantly more inbred than controls and that this increase was explained by the high level of inbreeding of a few cases whose parents were related at the first-cousin level. This could possibly indicate the implication of a recessive element in a small subset of AD cases in the Saguenay population. We also found that late-onset epsilon 4+ cases were significantly more closely related among themselves than with controls. This increase in kinship may be attributable to the presence of the epsilon 4 allele or to some other unidentified genetic factor possibly acting in conjunction with APOE-epsilon 4.

Structural correlates of cognitive deficits in a selected group of patients with Alzheimer's disease.

OBJECTIVE: The objective of this study was to correlate the densities of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 10 patients with Alzheimer's disease (AD) with comprehensive neuropsychological data obtained within 1 year of death. BACKGROUND: Clinicopathologic studies in AD have been essentially limited to correlate neuropathologic data with severity of dementia. Very few studies have addressed the correlations between distribution of lesions and specific cognitive deficits. This is partly due to the limitation imposed by the interval between the last neuropsychological evaluation and death. METHODS: Ten patients with a postmortem diagnosis of AD, with a mean age at death of 80.4+/-6.6 years and a mean duration of symptoms of 5.6+/-2.9 years, were selected for the study. All of these patients were submitted to neuropsychological testing within 1 year of death, including 17 tests assessing memory, language, visuoperceptual, visuospatial, and constructional abilities as well as limb praxis. The neuropathologic study was performed using a modified Bielschowsky technique. Mean densities of SPs and NFTs were determined in the hippocampal formation (CA1, subiculum, and parasubiculum) and in six neocortical areas (midfrontal, orbitofrontal, cingulum, fusiform gyrus, superior and inferior parietal cortices). Statistical correlations were determined between cognitive scores and SP and NFT densities. RESULTS: For NFTs, significant correlations emerged only between tangle density in CA1 and visuoperceptual scores. For SP density values, significant correlations were found between visuoperceptual tests and lesions in the subiculum and in the fusiform gyrus, significant correlations were found between language scores and SPs in the superior parietal cortex and between visuospatial deficits and lesions in the superior parietal cortex and fusiform gyrus. CONCLUSIONS: SPs in specific brain areas displayed a good correlation with the cognitive deficits detected in this selected group of AD patients. The association of fusiform gyrus and superior parietal lobule involvement with visuoperceptual and visuospatial deficits, respectively, is in agreement with current knowledge of the anatomic basis of visual processing.

Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their tau isoform distribution and phosphorylation.

Aggregated tau proteins constitute the basic matrix of neuronal inclusions specific to numerous neurodegenerative disorders. Monodimensional and two-dimensional Western blot analyses performed on cortical brain homogenates allowed discrimination between disease-specific tau protein profiles. These observations raised the issue of the physiopathological significance of such specificities. Alzheimer's disease (AD) pathological tau proteins (PTPs) (tau 74, 69, 64, 55) were compared with those of Pick's disease (PiD) (tau 64, 55) using a panel of antibodies against peptidic sequences of tau isoforms corresponding to exons 2, 3, and 10. AD and PiD could then be critically differentiated by the absence of translated tau isoforms with exon 10 in PiD PTPs, along with the absence of the phosphorylation site on Ser262. Immunohistochemical studies corroborate these findings. Indeed, Pick bodies were strongly immunostained by an anti-"exon 2" antibody but failed to reveal any anti-exon 10 reactive epitope. Tangles in AD contained exon 2, 3, and 10 epitopes. Altogether, our results demonstrated that Pick bodies develop within specific neuronal subsets that express specific patterns of 7 isoforms lacking exon 10 peptidic sequence. We conclude that neurodegenerative disorders imply attrition of selectively vulnerable neuronal subsets, a process revealed, and may be sustained by specific tau isoform patterns.

Educational level and neuropsychological heterogeneity in dementia of the Alzheimer type.

We retrospectively assessed the data from 24 patients with dementia of the Alzheimer type (DAT) who underwent comprehensive neuropsychological evaluations in order to determine whether there is a relationship between neuropsychological heterogeneity and educational level. Postmortem neuropathological examination results were made available for seven cases, confirming the diagnosis of DAT. Thirteen patients had < or = 8 years of schooling (less educated subgroup), and the other 11 had > or = 8 years (higher educated subgroup). There were no significant differences between the two subgroups regarding age and duration of symptoms. Performance within each subgroup was compared with that of a specific set of education-matched elderly controls. In the less educated subgroup, 10 patients evidenced a homogeneous pattern of cognitive impairment, with all cognitive areas being similarly affected. Conversely, 10 higher educated patients had at least one cognitive area relatively preserved in comparison with the others, characterizing a heterogeneous pattern of impairment. These data suggest that a high level of education may lead to a greater capacity to compensate for neuronal damage and determines specific patterns of cognitive impairment in DAT.

Symptoms and signs in dementia: synergy and antagonism.

This paper addresses the synergy and antagonism between symptoms and signs among 2,914 elderly Canadians diagnosed in 15 categories, including no cognitive impairment, cognitive impairment but no dementia, mild, moderate and severe forms of Alzheimer's disease and vascular dementia, 4 subtypes of possible Alzheimer's disease, Parkinson's dementia, unspecified other dementias and unclassified dementias Attention is paid to the relationships between symptoms and signs rather than conventional analyses which assume independent signs. We demonstrate that dementia progression and specific aetiologies have characteristic patterns of decline and destruction from the strong synergy that exists between symptoms and signs among the population with no cognitive impairment. These findings have potential implications for the incorporation of new diagnostic criteria into existing databases.

An algorithmic approach to the differential diagnosis of dementia.

The careful definition of cases is fundamental to diagnosis and to any study of cognitive, behavioural and functional problems in dementia. This paper presents an algorithmic approach which mimics a crucial component of diagnostic decision-making; symptoms and signs do not occur independently, but are conditioned on each other. First, we examine whether the conditioned items can be assembled to yield a differential diagnosis of dementia which corresponds to clinical diagnoses, and second, we explore whether subjects whose algorithmic profiles do not fit the clinical diagnoses form new discernable patterns. Such a technique offers two advantages: it allows for the development of validation protocols which are crucial to epidemiological studies, and it allows for the analysis of new patterns of signs and symptoms for emerging criteria of dementia subtypes. This approach has the potential to refine and enhance criteria for the differential diagnosis of dementia and to have an impact on case identification and assessment, particularly in large epidemiologic studies.

Alzheimer's disease: preliminary study of spatial distribution at birth place.

Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by a progressive loss of memory and the alteration of cognitive functions. At least three chromosomal segments have been associated with early-onset AD in genetic linkage studies. These results argue for a certain degree of heterogeneity in the genetic origin of some forms of AD, although environmental risk factors cannot be ruled out in late-onset AD. In this preliminary study, we analyzed the geographical distribution of the birth places of a sample of 235 AD cases born in a defined region of Quebec (Canada), between 1895 and 1935. We wished to test the hypothesis that risk factors acting at, or around birth place and time play a role in the etiology of AD. The field of study was divided into rural and urban areas. A reference population of live births was used to compute a measure of odds ratio (OR). The OR results showed a statistically significant excess of AD cases in the rural area as compared to the reference population. When stratified for sex, the OR results showed a global excess of female AD cases in both the rural and the urban areas. For men, only the urban area presented a statistically significant deficit. We also analyzed the structures of the genealogical kinships of the rural and urban sub-groups. Although AD cases from the rural sub-group were more closely related to each other than those from the urban one, removal of the kin pairs from the OR analysis seemed to have little effect on the rural/urban distribution of cases. Therefore, the OR results would not appear to be due primarily to a difference in the kinship structures of the two sub-groups. This could mean that some risk factors for AD afflict women more strongly than men, the effect being different depending on the urban or rural origin. However, potential biases such as a higher rate of report for women, differential migration between birth places or a differential mortality ratio between sexes could produce spurious results in the direction of what we have observed in this preliminary study.

Specific pathological Tau protein variants characterize Pick's disease.

Pick's disease (PiD) is characterized by a pan-laminar frontotemporal cortical atrophy, widespread degeneration of the white matter, chromatolytic neurons, and Pick bodies (PB). Microtubule-associated Tau proteins are the main cytoskeletal components modified during the neurodegenerative changes. In the present study, pathological alterations of Tau proteins were investigated in the brains of five PiD cases at both neuropathological and biochemical levels, using the monoclonal antibody AD2 which recognizes a phosphorylation-dependent Tau epitope and strongly labeled PB. A large number of cortical and subcortical regions were studied on frozen materials. Tau proteins were analyzed on mono- and two-dimensional gel electrophoreses using a quantitative western blot approach. In all specimens, a 55 and 64 kDa Tau doublet was observed in limbic, frontal, and temporal cortices as well as in striatum and substantia nigra. In contract, Alzheimer's disease (AD) brains are characterized by the presence of the 55, 64, and 69 kDa Tau triplet whereas the 64 and 69 kDa doublet is more typical of the progressive supranuclear palsy and corticobasal degeneration. Thus, the 55 and 64 kDa doublet appears to be specific to PiD, less acidic than AD Tau proteins, and well correlated with the presence of PB.

Season of birth and Alzheimer's disease: a population-based study in Saguenay-Lac-St-Jean/Québec (IMAGE Project).

The birth distribution of 399 cases of Alzheimer's disease (AD) identified in the region of Saguenay-Lac-St-Jean (Québec) was compared with that of: (a) the population currently living in the area; and (b) the population born during the same period in the same area. AD cases have been recruited since 1986 by the IMAGE Project. Cases and controls were grouped according to the month of birth and according to the day of birth using density estimation. Analyses showed a significant deficit of births in the month of May. We believe these preliminary results deserve further attention and we suggest two possible explanations that could lead to a deficit of AD births at specific periods during the year.

Distribution of brain cytochrome oxidase activity in various neurodegenerative diseases.

Cytochrome oxidase (CO) is the terminal complex of the mitochondrial respiratory chain which generates ATP by oxidative phosphorylation. We have measured CO activity in six different brain regions of patients with senile dementia of Alzheimer type (SDAT, n = 10), presenile dementia of Alzheimer type (PDAT, n = 10), Lewy body dementia with SDAT (LBD, n = 5), cerebrovascular dementia (CVD, n = 10), Parkinson dementia (PD, n = 5), and in controls (n = 8), as all confirmed by neuropathological evaluation. CO activity was lower in the frontal and parietal cortex of SDAT patients compared to controls. Patients with PDAT, LBD, CVD or PD showed no significant reduction of the enzymatic activity in the six regions studied. Our results show that reduced CO activity might play a role in the physiopathology of senile dementia of Alzheimer type.

Neurodegenerative diseases and risk factors: a literature review.

Degenerative diseases of the central nervous system are significant causes of mortality among elderly people in industrialized countries. For the most part, the causes of these diseases are unknown. It is also very difficult to diagnose this type of disease quickly and accurately. This article reviews the epidemiological research on the principal neurodegenerative disorders, focusing on geographical, hereditary and viral and toxicological exposure correlates. We look in particular at the effect of exposure to toxins as well as the effect that deficiencies of elements such as calcium and selenium could have on the development of these neurological diseases. We also consider the possible protectionist effect of some variables on the development of certain neurological diseases.

Apo E allele frequencies in Alzheimer's disease, Lewy body dementia, Alzheimer's disease with cerebrovascular disease and vascular dementia.

Apolipoprotein (Apo E) was genotyped using a fluorescent PCR-RFLP assay in 187 patients with a probable or possible clinical diagnosis of sporadic Alzheimer's disease (AD) and in 166 autopsied patients with dementia (21 presenile AD, 70 senile AD, 18 Lewy body dementia (LBD), 38 AD with cerebrovascular disease (AD-CVD), 19 vascular dementia). The relative epsilon 4 allele frequency was 0.472 in LBD, 0.513 in AD-CVD, 0.405 in presenile AD, 0.364 in senile AD, and 0.079 in vascular dementia. The relative epsilon 2 allele frequency was 0.211 in vascular dementia, 0.083 in LBD, 0.047 in presenile AD, 0.100 in senile AD and 0.039 in AD with CVD. We infer that apo E is a major risk factor for structural phenotypes of dementia involving AD, alone or in conjunction with another pathology. In addition, the epsilon 2 allele is likely to represent a risk factor for vascular morbidity, as the relative epsilon 2 allele frequency was 0.211 in patients with vascular dementia compared with 0.144 in elderly controls.