Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in ...transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.
Alzheimer's disease (AD) is a neurodegenerative disorder histologically defined by the cerebral accumulation of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau ...proteins. Loss of basal forebrain cholinergic neurons is another hallmark of the disease thought to contribute to the cognitive dysfunctions. To this date, the mechanisms underlying cholinergic neurons degeneration remain uncertain. The present study aimed to investigate the relationship between neurofibrillary degeneration and cholinergic defects in AD using THY-Tau22 transgenic mouse model exhibiting a major hippocampal AD-like tau pathology and hyperphosphorylated tau species in the septohippocampal pathway. Here, we report that at a time THY-Tau22 mice display strong reference memory alterations, the retrograde transport of fluorogold through the septohippocampal pathway is altered. This impairment is associated with a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum. Analysis of nerve growth factor (NGF) levels supports an accumulation of the mature neurotrophin in the hippocampus of THY-Tau22 mice, consistent with a decrease of its uptake or retrograde transport by cholinergic terminals. Finally, our data strongly support that tau pathology could be instrumental in the cholinergic neuronal loss observed in AD.
Summary The Ewing-like variation of adamantinoma is a rare entity, leading to challenge its differential diagnosis, notably with Ewing's sarcoma. We are reporting a case of a 20-year-old male who ...presented with swelling in the left leg that had progressed over a 2-year period. X-rays revealed a tumour in the tibia that was intracortical, osteolytic, multilocular and invaded the soft tissues. A surgical biopsy was performed. Histopathology examination showed a tumour growth with small round cells expressing CD99. A diagnosis of Ewing's sarcoma was made. Since the patient declined surgical treatment, chemotherapy was administered. Two years later, the patient returned because the tumour had grown in size. A second biopsy was performed. Microscopic evaluation showed a tumour growth with osteofibrous and epithelial components, which expressed pankeratin and vimentin, but was negative for CD99. A diagnosis of Ewing-like adamantinoma was made.
Increasing evidence suggests that an inhibition of the proteasome, as demonstrated in Parkinson’s disease, might be involved in Alzheimer’s disease. In this disease and other Tauopathies, Tau ...proteins are hyperphosphorylated and aggregated within degenerating neurons. In this state, Tau is also ubiquitinated, suggesting that the proteasome might be involved in Tau proteolysis. Thus, to investigate if proteasome inhibition leads to accumulation, hyperphosphorylation and aggregation of Tau, we used neuroblastoma cells overexpressing Tau proteins. Surprisingly, we showed that the inhibition of the proteasome led to a bidirectional degradation of Tau. Following this result, the cellular mechanisms that may degrade Tau were investigated.
Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with ...behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation.
Inhibin B is a testicular peptide hormone that regulates FSH secretion in a negative feedback loop. Inhibin B is a dimer of an α and a βB subunit. In adult testes, the cellular site of production is ...still controversial, and it was hypothesized that germ cells contribute to inhibin B production. To determine which cell types in the testes may produce inhibin B, the immunohistochemical localization of the two subunits of inhibin B were examined in adult testicular biopsies with normal spermatogenesis, spermatogenic arrest, or Sertoli cell only (SCO) tubules. Moreover, using in situ hybridization with mRNA probes, the mRNA expression patterns of inhibin α and inhibin/activin βB subunits have been investigated. In all testes, Sertoli cells and Leydig cells showed positive immunostaining for inhibin α subunit and expressed inhibin α subunit mRNA. Using inhibin βB subunit immunoserum on testes with normal spermatogenesis and with spermatogenic arrest, intense labeling was located in germ cells from pachytene spermatocytes to round spermatids but not in Sertoli cells. Inhibin βB subunit mRNA expression was intense in germ cells from spermatogonia to round spermatids and in Sertoli cells in these testes. In testes with SCO, high inhibin βB subunit mRNA labeling density was observed in both Sertoli cells and Leydig cells, whereas βB subunit immunostaining was negative for Sertoli cells and faintly positive for Leydig cells. These results agree with the recent opinion that inhibin B in adult men is possibly a joint product of Sertoli cells and germ cells.
The peptidyl prolyl cis–trans isomerase Pin1 and the Inhibitor of Apoptosis Protein (IAP) Survivin are two major proteins involved in cancer. They both modulate apoptosis, mitosis, centrosome ...duplication and neuronal development but until now no functional relationship has been reported between these two proteins. We tested Pin1-induced regulation of Survivin in neuroblastoma cells. Pin1 overexpression in SY5Y neuroblastoma cells decreased Survivin levels. Immunocytochemical studies indicated that they partially co-localized in interphase and mitotic cells. Co-immunoprecipitation further demonstrates the existence of a Pin1/Survivin complex. Pin1-induced effect on Survivin was confirmed in COS cells. RT-PCR and mutagenesis experiments suggested that this Pin1-induced decrease of Survivin occurred at the protein level. Survivin downregulation depended on the binding ability of Pin1 but was not related to the single Thr–Pro site, suggesting an indirect relationship into a protein complex. Finally, this functional regulation of Survivin by Pin1 is reciprocal since Pin1 silencing led to an increase in Survivin levels. The characterization of this functional relationship between Pin1 and Survivin might help to better understand mitosis control and cancer mechanisms.
Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 ...transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
Recent studies from our laboratory suggested that the vascular
endothelium of the median eminence was involved via nitric oxide
secretion in the modulation of GnRH release during the estrous cycle.
...To further investigate that issue, we studied the variations of
endothelial nitric oxide synthase protein and mRNA in the median
eminence of female rats killed at different time points of the day
and/or of the estrous cycle. Endothelial nitric oxide synthase protein
levels were measured by Western blot, and endothelial nitric oxide
synthase mRNA analysis was performed with semiquantitative RT-PCR (for
each time point, n = 4). The results revealed that endothelial
nitric oxide synthase synthesis varied markedly across the estrous
cycle. Indeed, endothelial nitric oxide synthase protein (n = 20)
and mRNA (n = 16) levels increase significantly on 0800 h and
1600 h proestrus compared with 1400 h diestrus II. In a
second step, quantification analysis were made in median eminence
obtained from ovariectomized and ovariectomized, E2 benzoate primed
rat. The results show a significant increase in expression of
endothelial nitric oxide synthase protein as well as endothelial nitric
oxide synthase mRNA in ovx-E2 primed rat median eminence. Concurrently,
the levels of the cav-1 protein, a specific endogenous inhibitor of
endothelial nitric oxide synthase, were measured in median eminence
during estrous cycle and in ME from ovx and ovx-E2 primed rats. A
significant decrease of median eminence cav-1 was noted on 1600 h
proestrus and in ovx-E2 primed rats when compared with 1400 h
diestrus II and ovx, respectively. Altogether, these results strongly
suggest that high NO release from median eminence observed on proestrus
may be due to an increase of endothelial nitric oxide synthase
expression and a decrease of the cav-1 protein levels. These findings
demonstrate that E2 is able to modulate endothelial nitric oxide
synthase and cav-1 expression both during the estrous cycle and in
experimental conditions and consequently reinforce the idea that nitric
oxide acting on GnRH release, is essentially endothelial in origin.
These results may also imply that variations of endothelial nitric
oxide synthase expression are essential for the pulsatile/cyclic nitric
oxide median eminence release observed in a previous study.
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