Association between acetylcholinesterase and beta-amyloid peptide in Alzheimer's cerebrospinal fluid

The altered expression of acetylcholinesterase (AChE) in the brains of patients with Alzheimer's disease (AD) has raised much interest of late. Despite an overall decrease in the AD brain, the activity of AChE increases around beta-amyloid plaques and indeed, the beta-amyloid peptide (Abeta) can influence AChE levels. Such evidence stimulated our interest in the possibility that the levels of AChE and amyloid might vary together in AD. We previously found that the different AChE forms present in both the brain and in the cerebrospinal fluid (CSF) of AD patients varied in conjunction with abnormal glycosylation. Thus, the alterations in glycosylation are correlated with the accumulation of a minor subspecies of AChE monomers. We also recently analysed whether long-term exposure to the cholinesterase inhibitor (ChE-I) donepezil influences the AChE species found in AD CSF. The marked increase in CSF-AChE activity in AD patients following long-term treatment with donepezil was not paralleled by a rise in this subset of light variants. Hence, the correlation with the levels of CSF-Abeta is unique to these AChE species in patients receiving such treatment. The aim of this report is to review the links between AChE and beta-amyloid, and to discuss the significance of the responses of the distinct AChE species to ChE-I during the treatment of AD.     

The Water-Soluble Chitosan Derivative,N-Methylene Phosphonic Chitosan,Is an Effective Fungicide against the Phytopathogen Fusarium eumartii

Chitosan has been considered an environmental-friendly polymer. However, its use in agriculture has not been extended yet due to its relatively low solubility in water. N-Methylene phosphonic chitosan (NMPC) is a water-soluble derivative prepared by adding a phosphonic group to chitosan. This study demonstrates that NMPC has a fungicidal effect on the phytopathogenic fungus Fusarium solani f. sp. eumartii (F. eumartii) judged by the inhibition of F. eumartti mycelial growth and spore germination. NMPC affected fungal membrane permeability, reactive oxygen species production, and cell death. Also, this chitosan-derivative exerted antifungal effects against two other phytopathogens, Botrytis cinerea, and Phytophthora infestans. NMPC did not affect tomato cell viability at the same doses applied to these phytopathogens to exert fungicide action. In addition to water solubility, the selective biological cytotoxicity of NMPC adds value in its application as an antimicrobial agent in agriculture.     

Role of sex hormones in lung cancer

Lung cancer represents the world’s leading cause of cancer deaths. Sex differences in the incidence and mortality rates for various types of lung cancers have been identified, but the biological and endocrine mechanisms implicated in these disparities have not yet been determined. While some cancers such as lung adenocarcinoma are more commonly found among women than men, others like squamous cell carcinoma display the opposite pattern or show no sex differences. Associations of tobacco product use rates, susceptibility to carcinogens, occupational exposures, and indoor and outdoor air pollution have also been linked to differential rates of lung cancer occurrence and mortality between sexes. While roles for sex hormones in other types of cancers affecting women or men have been identified and described, little is known about the influence of sex hormones in lung cancer. One potential mechanism identified to date is the synergism between estrogen and some tobacco compounds, and oncogene mutations, in inducing the expression of metabolic enzymes, leading to enhanced formation of reactive oxygen species and DNA adducts, and subsequent lung carcinogenesis. In this review, we present the literature available regarding sex differences in cancer rates, associations of male and female sex hormones with lung cancer, the influence of exogenous hormone therapy in women, and potential mechanisms mediated by male and female sex hormone receptors in lung carcinogenesis. The influence of biological sex on lung disease has recently been established, thus new research incorporating this variable will shed light on the mechanisms behind the observed disparities in lung cancer rates, and potentially lead to the development of new therapeutics to treat this devastating disease.     

Impact of proestrous milieu on expression of orexin receptors and prepro-orexin in rat hypothalamus and hypophysis: actions of Cetrorelix and Nembutal

Orexins and their receptors OX1 and OX2 regulate energy balance and the sleep-wake cycle. We studied the expression of prepro-orexin (PPO), OX1, and OX2 in brain and pituitary under the influence of the hormonal status in adult rats. Primarily, PPO, OX1, and OX2 expression was determined in Sprague-Dawley female cycling rats during proestrus and in males. Animals were killed at 2-h intervals. Anterior (AH) and mediobasal (MBH) hypothalamus, anterior pituitary (P), and frontoparietal cortex (CC) were homogenized in TRIzol, and mRNAs were obtained for screening of PPO, OX1, OX2 expression by semiquantitative RT-PCR. Main findings were confirmed and extended to all days of the cycle by quantitative real-time RT-PCR. Hormones and food consumption were determined. Finally, OX1, OX2, and PPO were measured by real-time RT-PCR in tissues collected at 1900 of proestrus after treatments at 1400 with ovulation-blocking agents Cetrorelix or pentobarbital. OX1 and OX2 expression increased at least threefold in AH, MBH, and P, but not in CC, between 1700 and 2300 of proestrus, without variations in estrus, diestrus, or in males. PPO in AH and MBH showed a fourfold or higher increase only during proestrus afternoon. Cetrorelix or pentobarbital prevented increases of OX1 and OX2 only in the pituitary and blunted gonadotropin surges, but left OX1, OX2, and PPO brain expression unchanged. Reproduction, energy balance, and sleep-wake cycle are integrated. Here, we demonstrate that, in the physiological neuroendocrine condition leading to ovulation, information to the orexinergic system acts in hypothalamus and pituitary by different mechanisms.     

Gonadal steroids modulated hypocretin/orexin type-1 receptor expression in a brain region, sex and daytime specific manner

Orexins A and B (hypocretins A and B) are regulatory peptides that control a variety of neuroendocrine and autonomic functions including feeding and sleep-wakefulness. Previously, we described a clear relationship between the hormonal milieu of the estrous cycle and the mRNA expression of the components of the orexinergic system, in the hypothalamus, pituitary and ovary. Here, we investigate whether steroid hormones are involved in the modulation of the hypocretin/orexin type-1 receptor expression at the protein level, and its time of the day dependence, in hypothalamus and pituitary of castrated male and female rats and castrated receiving hormone replacement.Orchidectomy decreased the hypocretin/orexin type-1 receptor expression in anterior hypothalamus, but not in mediobasal hypothalamus or cortex; in pituitary this treatment resulted in an increase. Testosterone and dihydrotestosterone were able to restore receptor expression and gonadotropins.In females, pituitary and ovarian hormones increased during proestrous afternoon. Hypocretin/orexin type-1 receptor expression was higher at 19:00 of proestrus in hypothalamus and pituitary. Ovariectomized treated with estradiol or oil and sacrificed at 11:00 h showed the receptor expression similar to 11:00 h of proestrus in hypothalamus and pituitary. At 19:00 h, low expression persisted in these areas in oil-treated ovariectomized rats; in contrast, estradiol replacement increased the expression to high levels of normal cycling rats at 19:00 h.Sexual steroids modulate the orexinergic system and the anatomical regions, hormones and times of the day all have to be considered when the roles of orexins, and probably other peptides, are under consideration.     

Asthma,atopy, and exercise: Sex differences in exercise-induced bronchoconstriction

Asthma is a chronic inflammatory lung disease affecting approximately 7.7% of the US population. Sex differences in the prevalence, incidence, and severity of asthma have been widely described throughout the lifespan, showing higher rates in boys than girls before puberty, but a reversed pattern in adults. Asthma is often associated with atopy, i.e. the tendency to develop allergic diseases, and can be worsened by environmental stimuli and/or exercise. While not exclusive to patients with asthma, exercise-induced bronchoconstriction (EIB) is a common complication of athletes and individuals who exercise regularly. Currently, there is limited research on sex differences in EIB and its relationship with atopy and asthma in men and women. In this minireview, we summarize the available literature on this topic. Overall, the collective knowledge supports the notion that physiological changes triggered during exercise affect males and females differently, suggesting an interaction among sex, exercise, sex hormones, and atopic status in the course of EIB pathophysiology. Understanding these differences is important to provide personalized management plans to men and women who exercise regularly and suffer from underlying asthma and/or atopy.     

Presenilin 1 interacts with acetylcholinesterase and alters its enzymatic activity and glycosylation

Presenilin 1 (PS1) plays a critical role in the gamma-secretase processing of the amyloid precursor protein to generate the beta-amyloid peptide, which accumulates in plaques in the pathogenesis of Alzheimer's disease (AD). Mutations in PS1 cause early onset AD, and proteins that interact with PS1 are of major functional importance. We report here the coimmunoprecipitation of PS1 and acetylcholinesterase (AChE), an enzyme associated with amyloid plaques. Binding occurs through PS1 N-terminal fragment independent of the peripheral binding site of AChE. Subcellular colocalization of PS1 and AChE in cultured cells and coexpression patterns of PS1 and AChE in brain sections from controls and subjects with sporadic or familial AD indicated that PS1 and AChE are located in the same intracellular compartments, including the perinuclear compartments. A PS1-A246E pathogenic mutation expressed in transgenic mice leads to decreased AChE activity and alteration of AChE glycosylation and the peripheral binding site, which may reflect a shift in protein conformation and disturbed AChE maturation. In both the transgenic mice and humans, mutant PS1 impairs coimmunoprecipitation with AChE. The results indicate that PS1 can interact with AChE and influence its expression, supporting the notion of cholinergic-amyloid interrelationships.     

Association between acetylcholinesterase and β-amyloid peptide in Alzheimer's cerebrospinal fluid

The altered expression of acetylcholinesterase (AChE) in the brains of patients with Alzheimer's disease (AD) has raised much interest of late. Despite an overall decrease in the AD brain, the activity of AChE increases around β-amyloid plaques and indeed, the β-amyloid peptide (Aβ) can influence AChE levels. Such evidence stimulated our interest in the possibility that the levels of AChE and amyloid might vary together in AD. We previously found that the different AChE forms present in both the brain and in the cerebrospinal fluid (CSF) of AD patients varied in conjunction with abnormal glycosylation. Thus, the alterations in glycosylation are correlated with the accumulation of a minor subspecies of AChE monomers. We also recently analysed whether long-term exposure to the cholinesterase inhibitor (ChE-I) donepezil influences the AChE species found in AD CSF. The marked increase in CSF-AChE activity in AD patients following long-term treatment with donepezil was not paralleled by a rise in this subset of light variants. Hence, the correlation with the levels of CSF-Aβ is unique to these AChE species in patients receiving such treatment. The aim of this report is to review the links between AChE and β-amyloid, and to discuss the significance of the responses of the distinct AChE species to ChE-I during the treatment of AD.     

Cerebrospinal fluid acetylcholinesterase changes after treatment with donepezil in patients with Alzheimer's disease

We analyzed whether donepezil differently influences acetylcholinesterase (AChE) variants from cerebrospinal fluid (CSF) in patients with Alzheimer's disease (AD) after long-term treatment. Overall CSF-AChE activity in AD patients before treatment was not different from controls, but the ratio between the major tetrameric form, G(4), and the smaller G(1) and G(2) species was significantly lower. AChE levels at study outset were found to correlate positively with beta-amyloid (1-42) (Abeta42). When patients were re-examined after 12 months treatment with donepezil, there was a remarkable increase in both the G(4) and the lighter species of CSF AChE. As compared with placebo, donepezil caused decreases in the percentage of AChE that failed to bind to the lectin concanavalin A and the antibody AE1. These non-binding species comprised primarily a small subset of G(1) and G(2) forms. In treated patients, these light variants were the only subset of CSF AChE that correlated with CSF-Abeta42 levels. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that a 77-kDa band, attributed in part to inactive AChE, was lower in AD patients than in controls. Unlike enzyme activity, the intensity of this band did not increase after donepezil treatment. The varying responses of different AChE species to ChE-I treatment suggest different modes of regulation, which may have therapeutic implications.     

Mean reproductive traits of fungal assemblages are correlated with resource availability

Organisms have evolved a fascinating variety of strategies and organs for successful reproduction. Fruit bodies are the reproductive organ of fungi and vary considerably in size and shape among species. Our understanding of the mechanisms underlying the differences in fruit body size among species is still limited. Fruit bodies of saprotrophic fungi are smaller than those of mutualistic ectomycorrhizal fungi. If differences in fruit body size are determined by carbon acquisition, then mean reproductive traits of saprotrophic and ectomycorrhizal fungi assemblages should vary differently along gradients of resource availability as carbon acquisition seems more unpredictable and costly for saprotrophs than for ectomycorrhizal fungi. Here, we used 48 local inventories of fungal fruit bodies (plot size: 0.02 ha each) sampled along a gradient of resource availability (growing stock) across 3 years in the Bavarian Forest National Park in Germany to investigate regional and local factors that might influence the distribution of species with different reproductive traits, particularly fruit body size. As predicted, mean fruit body size of local assemblages of saprotrophic fungi was smaller than expected from the distribution of traits of the regional species pool across central and northern Europe, whereas that of ectomycorrhizal fungi did not differ from random expectation. Furthermore and also as expected, mean fruit body size of assemblages of saprotrophic fungi was significantly smaller than for assemblages of ectomycorrhizal species. However, mean fruit body sizes of not only saprotrophic species but also ectomycorrhizal species increased with resource availability, and the mean number of fruit bodies of both assemblages decreased. Our results indicate that the differences in carbon acquisition between saprotrophs and ectomycorrhizal species lead to differences in basic reproductive strategies, with implications for the breadth of their distribution. However, the differences in resource acquisition cannot explain detailed species distribution patterns at a finer, local scale based on their reproductive traits.