39 research outputs found
Endothelial LRP1 transports amyloid-β1-42 across the blood-brain barrier
According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor-related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-beta (A beta) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in A beta transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic A beta clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slo1c1-CreER(Tz) Lrp1(fl/fl) mice) and used these mice to accurately evaluate LRP1-mediated A beta BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [I-125] A beta(1-42). Additionally, in the 5xFAD mouse model of AD, brain endothelial-specific Lrp1 deletion reduced plasma A beta levels and elevated soluble brain A beta, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic AD elimination via the BBB. Together, our results suggest that receptor-mediated A beta BBB clearance may be a potential target for treatment and prevention of A beta brain accumulation in AD
FGF-2 Deficiency Does Not Influence FGF Ligand and Receptor Expression during Development of the Nigrostriatal System
Secreted proteins of the fibroblast growth factor (FGF) family play important roles during development of various organ systems. A detailed knowledge of their temporal and spatial expression profiles, especially of closely related FGF family members, are essential to further identification of specific functions in distinct tissues. In the central nervous system dopaminergic neurons of the substantia nigra and their axonal projections into the striatum progressively degenerate in Parkinson's disease. In contrast, FGF-2 deficient mice display increased numbers of dopaminergic neurons. In this study, we determined the expression profiles of all 22 FGF-ligands and 10 FGF-receptor isoforms, in order to clarify, if FGF-2 deficiency leads to compensatory up-regulation of other FGFs in the nigrostriatal system. Three tissues, ventral mesencephalon (VM), striatum (STR) and as reference tissue spinal cord (SC) of wild-type and FGF-2 deficient mice at four developmental stages E14.5, P0, P28, and adult were comparatively analyzed by quantitative RT-PCR. As no differences between the genotypes were observed, a compensatory up-regulation can be excluded. Moreover, this analysis revealed that the majority of FGF-ligands (18/22) and FGF-receptors (9/10) are expressed during normal development of the nigrostriatal system and identified dynamic changes for some family members. By comparing relative expression level changes to SC reference tissue, general alterations in all 3 tissues, such as increased expression of FGF-1, -2, -22, FgfR-2c, -3c and decreased expression of FGF-13 during postnatal development were identified. Further, specific changes affecting only one tissue, such as increased FGF-16 (STR) or decreased FGF-17 (VM) expression, or two tissues, such as decreased expression of FGF-8 (VM, STR) and FGF-15 (SC, VM) were found. Moreover, 3 developmentally down-regulated FGFs (FGF-8b, FGF-15, FGF-17a) were functionally characterized by plasmid-based over-expression in dissociated E11.5 VM cell cultures, however, such a continuous exposure had no influence on the yield of dopaminergic neurons in vitro
The epithelial cholinergic system of the airways
Acetylcholine (ACh), a classical transmitter of parasympathetic nerve fibres in the airways, is also synthesized by a large number of non-neuronal cells, including airway surface epithelial cells. Strongest expression of cholinergic traits is observed in neuroendocrine and brush cells but other epithelial cell types—ciliated, basal and secretory—are cholinergic as well. There is cell type-specific expression of the molecular pathways of ACh release, including both the vesicular storage and exocytotic release known from neurons, and transmembrane release from the cytosol via organic cation transporters. The subcellular distribution of the ACh release machineries suggests luminal release from ciliated and secretory cells, and basolateral release from neuroendocrine cells. The scenario as known so far strongly suggests a local auto-/paracrine role of epithelial ACh in regulating various aspects on the innate mucosal defence mechanisms, including mucociliary clearance, regulation of macrophage function and modulation of sensory nerve fibre activity. The proliferative effects of ACh gain importance in recently identified ACh receptor disorders conferring susceptibility to lung cancer. The cell type-specific molecular diversity of the epithelial ACh synthesis and release machinery implies that it is differently regulated than neuronal ACh release and can be specifically targeted by appropriate drugs
Treatment delay and radiological errors in patients with bone metastases
During routine investigations, we are surprised to find that therapy for bone metastases is sometimes delayed for a considerable period of time. To determine the extent of this delay and its causes, we reviewed the medical records of symptomatic patients seen at our hospital who had been recently diagnosed as having bone metastases for the last four years. The treatment delay was defined as the interval between presentation with symptoms and definitive treatment for bone metastases. The diagnostic delay was defined as the interval between presentation with symptoms and diagnosis of bone metastases. The results of diagnostic radiological examinations were also reviewed for errors. The study population included 76 males and 34 females with a median age of 66 years. Most bone metastases were diagnosed radiologically. Over 75% of patients were treated with radiotherapy. The treatment delay ranged from 2 to 307 days, with a mean of 53.3 days. In 490 radiological studies reviewed, we identified 166 (33.9%) errors concerning 62 (56.4%) patients. The diagnostic delay was significantly longer for patients with radiological errors than for patients without radiological errors (P < 0.001), and much of it was due to radiological errors. In conclusion, the treatment delay in patients with symptomatic bone metastases was much longer than expected, and much of it was caused by radiological errors. Considerable efforts should therefore be made to more carefully examine the radiological studies in order to ensure prompt treatment of bone metastases
Proton magnetic resonance spectroscopy assessment of metabolite status of the anterior cingulate cortex in chronic pain patients and healthy controls
Takahiro Ito,1 Sachiko Tanaka-Mizuno,2,3 Narihito Iwashita,4 Ikuo Tooyama,5 Akihiko Shiino,6 Katsuyuki Miura,1,7 Sei Fukui4 1Department of Public Health, Shiga University of Medical Science, 2Department of Medical Statistics, Shiga University of Medical Science, Otsu, Japan; 3The Center for Data Science Education and Research, Shiga University, Hikone, Japan; 4Department of Anesthesiology, Interdisciplinary Pain Management Center, Shiga University of Medical Science Hospital, 5Molecular Neuroscience Research Center, Shiga University of Medical Science, 6Biomedical MR Science Center, Shiga University of Medical Science, 7Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan Background: Chronic pain is a common cause of reduced quality of life. Recent studies suggest that chronic pain patients have a different brain neurometabolic status to healthy people. Proton magnetic resonance spectroscopy (1H-MRS) can determine the concentrations of metabolites in a specific region of the brain without being invasive. Patients and methods: We recruited 56 chronic pain patients and 60 healthy controls to compare brain metabolic characteristics. The concentrations of glutamic acid (Glu), myo-inositol (Ins), N-acetylaspartate (NAA), Glu + glutamine (Glx), and creatine + phosphocreatine (total creatine [tCr]) in the anterior cingulate cortex of participants were measured using 1H-MRS. We used age- and gender-adjusted general linear models and receiver-operating characteristic analyses for this investigation. Patients were also assessed using the Hospital Anxiety and Depression Scale (HADS) to reveal the existence of any mental health issues. Results: Our analysis indicates that pain patients have statistically significantly higher levels of Glu/tCr (p=0.039) and Glx/tCr (p<0.001) and lower levels of NAA/tCr than controls, although this did not reach statistical significance (p=0.052). Receiver-operating characteristic analysis performed on the combination of Glx/tCr, Ins/tCr, and NAA/tCr effectively discriminated chronic pain patients from healthy controls. Patients with higher HADS-Depression scores had increased Glx/rCr levels (p=0.015), and those with higher HADS-Anxiety scores had increased NAA/tCr levels (p=0.018). Conclusion: Chronic pain patients have a different metabolite status in the anterior cingulate cortex to controls. Within the pain patient group, HADS scores had a positive relationship with NAA/tCr and Glx/tCr levels. 1H-MRS successfully detected metabolic changes in patients’ brains in a noninvasive manner, revealing its potential as a superior diagnostic tool for pain patients. Keywords: chronic pain, magnetic resonance spectroscopy, glutamic acid, myo-inositol, N-acetylaspartate, creatine 
Deposition of Alpha2-Macroglobulin in Fibrillar Type of Senile Plaques in the Brain of PS/APP-Transgenic Mice.
First emission studies of Tc2X82− systems (X = Cl, Br)
The emission spectra of the solids [n-Bu4N]2Tc2X8 (X = Cl, Br) have been investigated at room temperature and 77 K. In each case, the emission originates in the 1δ–δ* excited state, as with the rhenium homologues, but has a shorter lifetime