S100A1 and S100B: Novel Drug Targets for Alzheimer's Disease Therapy

Numerous factors/gene products, including S100A1 and S100B, have been implicated in the onset and progression of Alzheimer's disease (AD). However, deciphering S100A1/S100B's role in AD has been hampered by their antipodal effects and ability to act as both intracellular calcium receptors and secreted neuropeptides. This study utilizes two approaches, genetic ablation and passive immunotherapy, to inhibit S100A1 and/or S100B in the PSAPP AD mouse model to ascertain the net contribution of these proteins to AD pathology. In addition, a combination of microarray profiling, post-array validation and bioinformatics were used to identify changes in miRNA expression in response to S100A1/S100B ablation. In 6 month old mice, S100B ablation resulted in a 3-fold decrease in cortical but not hippocampal plaque load while S100A1 ablation resulted in a 3.5-fold reduction in cortical and a 2.4-fold reduction in hippocampal plaque load. Interestingly, ablation of both S100A1 and S100B was synergistic resulting in an age-, region- and end point- specific manner. Diminished plaque load was accompanied by decreased GFAP-positive astrocytes and Iba-1 positive microglia. The effects of S100A1/S100B on plaque load were not limited to early stages of plaque deposition. Even though older (12 month old) PSAPP animals had over 6-fold increase in plaque load, S100A1 or S100A1/S100B ablation still diminished cortical/hippocampal plaque load by 60-65%. Similar results were observed when passive immunotherapy was used to inhibit S100A1/S100B function. Anti-S100 treatment of mice from 3-6 months of age decreased cortical/hippocampal plaque load, and decreased cortical but not hippocampal GFAP staining. The effects of passive immunotherapy with S100A1/S100B antibodies were not limited to pre-plaque treatment. Anti-S100 treated mice from 6-9 months of age exhibited decreased cortical, but not hippocampal, plaque load and cortical/hippocampal GFAP staining. In addition, these S100A1/S100B mediated decreases were accompanied by downregulated expression of miR- 448, miR-133a, miR-204, and miR-206 as well as upregulated expression of miR-34a. Collectively, these data demonstrate that inhibition of S100A1 and S100B synergistically reduce AD pathology and suggest that the detrimental gain of function of S100A1/S100B contributes to AD. Therefore, development of drugs to inhibit S100 function in patients will be beneficial in the treatment of AD and slowing disease progression

PSAPP mice exhibit regionally selective reductions in gliosis and plaque deposition in response to S100B ablation

<p>Abstract</p> <p>Background</p> <p>Numerous studies have reported that increased expression of S100B, an intracellular Ca²⁺receptor protein and secreted neuropeptide, exacerbates Alzheimer's disease (AD) pathology. However, the ability of S100B inhibitors to prevent/reverse AD histopathology remains controversial. This study examines the effect of S100B ablation on <it>in vivo </it>plaque load, gliosis and dystrophic neurons.</p> <p>Methods</p> <p>Because S100B-specific inhibitors are not available, genetic ablation was used to inhibit S100B function in the PSAPP AD mouse model. The PSAPP/S100B^-/-line was generated by crossing PSAPP double transgenic males with S100B^-/-females and maintained as PSAPP/S100B^+/-crosses. Congo red staining was used to quantify plaque load, plaque number and plaque size in 6 month old PSAPP and PSAPP/S100B^-/-littermates. The microglial marker Iba1 and astrocytic marker glial fibrillary acidic protein (GFAP) were used to quantify gliosis. Dystrophic neurons were detected with the phospho-tau antibody AT8. S100B immunohistochemistry was used to assess the spatial distribution of S100B in the PSAPP line.</p> <p>Results</p> <p>PSAPP/S100B^-/-mice exhibited a regionally selective decrease in cortical but not hippocampal plaque load when compared to PSAPP littermates. This regionally selective reduction in plaque load was accompanied by decreases in plaque number, GFAP-positive astrocytes, Iba1-positive microglia and phospho-tau positive dystrophic neurons. These effects were not attributable to regional variability in the distribution of S100B. Hippocampal and cortical S100B immunoreactivity in PSAPP mice was associated with plaques and co-localized with astrocytes and microglia.</p> <p>Conclusions</p> <p>Collectively, these data support S100B inhibition as a novel strategy for reducing cortical plaque load, gliosis and neuronal dysfunction in AD and suggest that both extracellular as well as intracellular S100B contribute to AD histopathology.</p

Energy Expenditure Overestimation Bias in Elliptical Trainer Machine

Elliptical trainers are a common mode of aerobic exercise in recreationally active populations. Those with a weight loss goal might rely upon the energy expenditure (EE) estimation that many elliptical brands provide to keep track of calories (kcals) burned and make nutritional decisions. For this reason, it is important to evaluate the accuracy of the algorithms used by elliptical trainers to estimate EE. The purpose of this study was to compare EE estimates by a common brand of elliptical trainer to that measured using open circuit spirometry, at different combinations of resistance and pedal speed. Twenty subjects (10 male, 10 female; 34 ± 12 yr; 175.3 ± 10.7 cm; 77.1 ± 14.1 kg) consented to participate. Each completed three 15-min bouts of elliptical exercise on the same elliptical trainer, with at least 24 hr between exercise bouts. Pedal rates were held constant throughout each bout at 50, 60, or 70 RPM, and resistance was increased incrementally every 5 min from level 5 to 10 to 15. The different cadences were completed in a randomized order between participants. Expired gases were collected continuously throughout the 15 min. Heart rate, distance (mi), and EE from the elliptical readout were recorded every 1 min. RPE was collected twice per resistance level. A two-tailed paired samples t-test was used to compare elliptical EE to measured EE. A linear regression model was used to evaluate the ability of the elliptical EE to predict measured EE. Significance for all statistical measures was held at an alpha level of 0.05. The difference between EE estimates from the elliptical and measured VO2 was significant (p Measured EE = 0.95*(Elliptical EE) – 3.161 In conclusion, the elliptical trainer used for this study demonstrated a bias to overestimate EE. This should be taken into account by health/fitness professionals using these estimations to program for clients. There may be some variation in the EE correction regression depending on elliptical model, and proper machine calibration should be ensured

Multiyear Surveillance for Avian Influenza Virus in Waterfowl from Wintering Grounds, Texas Coast, USA

This surveillance can help in assessments of the prevalence of wild animal-to-human transmission

A physiological time analysis of the duration of the gonotrophic cycle of Anopheles pseudopunctipennis and its implications for malaria transmission in Bolivia

<p>Abstract</p> <p>Background</p> <p>The length of the gonotrophic cycle varies the vectorial capacity of a mosquito vector and therefore its exact estimation is important in epidemiological modelling. Because the gonotrophic cycle length depends on temperature, its estimation can be satisfactorily computed by means of physiological time analysis.</p> <p>Methods</p> <p>A model of physiological time was developed and calibrated for <it>Anopheles pseudopunctipennis</it>, one of the main malaria vectors in South America, using data from laboratory temperature controlled experiments. The model was validated under varying temperatures and could predict the time elapsed from blood engorgement to oviposition according to the temperature.</p> <p>Results</p> <p>In laboratory experiments, a batch of <it>An. pseudopunctipennis </it>fed at the same time may lay eggs during several consecutive nights (2–3 at high temperature and > 10 at low temperature). The model took into account such pattern and was used to predict the range of the gonotrophic cycle duration of <it>An. pseudopunctipennis </it>in four characteristic sites of Bolivia. It showed that the predicted cycle duration for <it>An. pseudopunctipennis </it>exhibited a seasonal pattern, with higher variances where climatic conditions were less stable. Predicted mean values of the (minimum) duration ranged from 3.3 days up to > 10 days, depending on the season and the geographical location. The analysis of ovaries development stages of field collected biting mosquitoes indicated that the phase 1 of Beklemishev might be of significant duration for <it>An. pseudopunctipennis</it>. The gonotrophic cycle length of <it>An. pseudopunctipennis </it>correlates with malaria transmission patterns observed in Bolivia which depend on locations and seasons.</p> <p>Conclusion</p> <p>A new presentation of cycle length results taking into account the number of ovipositing nights and the proportion of mosquitoes laying eggs is suggested. The present approach using physiological time analysis might serve as an outline to other similar studies and allows the inclusion of temperature effects on the gonotrophic cycle in transmission models. However, to better explore the effects of temperature on malaria transmission, the others parameters of the vectorial capacity should be included in the analysis and modelled accordingly.</p

Corrida em esteira e exercícios de força: efeitos agudos da ordem de realização sobre a hipotensão pós-exercício

Este estudo analisou as respostas de pressão arterial sistólica (PAS) e pressão arterial diastólica (PAD) após duas sessões de exercício concorrente realizado em diferentes ordens [aeróbio-força (AF), e força-aeróbio (FA)]. Quinze indivíduos normotensos foram submetidos a duas sessões de exercício realizadas em dias distintos na seguinte sequência AF e FA. A PAS e PAD foram medidas antes e a cada 15 min durante 60 min de recuperação pós-exercício. Houve hipotensão pós-exercício (HPE) para PAS, aos 30 min (-7,4 mmHg), 45 min (-12,14 mmHg) e 60 min (-15,14 mmHg) de recuperação na sessão AF. Já na FA houve HPE apenas aos 60 min (-8,34 mmHg) de recuperação. A variação da PAS e PAD entre as sessões revelou HPE maior aos 15 min, 45 min e 60 min na PAS; e aos 45 min na PAD comparando-se AF a FA. A realização de exercício aeróbio antes do de força resultou em maior HPE para adultos jovens

Preclinical evidence implicating corticotropin-releasing factor signaling in ethanol consumption and neuroadaptation

The results of many studies support the influence of the corticotropin-releasing factor (CRF) system on ethanol (EtOH) consumption and EtOH-induced neuroadaptations that are critical in the addiction process. This review summarizes the preclinical data in this area after first providing an overview of the components of the CRF system. This complex system involves hypothalamic and extra-hypothalamic mechanisms that play a role in the central and peripheral consequences of stressors, including EtOH and other drugs of abuse. In addition, several endogenous ligands and targets make up this system and show differences in their involvement in EtOH drinking and in the effects of chronic or repeated EtOH treatment. In general, genetic and pharmacological approaches paint a consistent picture of the importance of CRF signaling via type 1 CRF receptors (CRF1) in EtOH-induced neuroadaptations that result in higher levels of intake, encourage alcohol seeking during abstinence and alter EtOH sensitivity. Furthermore, genetic findings in rodents, non-human primates and humans have provided some evidence of associations of genetic polymorphisms in CRF-related genes with EtOH drinking, although additional data are needed. These results suggest that CRF1 antagonists have potential as pharmacotherapeutics for alcohol use disorders. However, given the broad and important role of these receptors in adaptation to environmental and other challenges, full antagonist effects may be too profound and consideration should be given to treatments with modulatory effects.The authors were supported by the Department of Veterans Affairs; NIH NIAAA grants P60AA010760, R24AA020245 and U01AA013519 and NIH NIDA grant P50DA018165, during the writing of this manuscript. The authors have no financial conflict of interest to disclose