7 research outputs found
The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer’s disease: a post-mortem autoradiographic study.
Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimer's disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[F-18]FMeNER-D-2. (S,S)-[F-18]FMeNER-D-2 appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[F-18]FMeNER-D-2 in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[F-18]FMeNER-D-2 as a molecular imaging biomarker in AD. (c) 2010 Elsevier Ltd. All rights reserved
Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications
This work was supported by a restricted research grant of Bayer AG
Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension
International audienceThe ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension
Identification of Tmem10/opalin as an oligodendrocyte enriched gene using expression profiling combined with genetic cell ablation
Oligodendrocytes form an insulating multilamellar structure
of compact myelin around axons, which allows efficient
and rapid propagation of action potentials. However, little
is known about the molecular mechanisms operating at the
onset of myelination and during maintenance of the myelin
sheath in the adult. Here we use a genetic cell ablation
approach combined with Affymetrix GeneChip microarrays
to identify a number of oligodendrocyte-enriched genes that
may play a key role in myelination. One of the ‘‘oligogenes’’
we cloned using this approach is Tmem10/Opalin, which
encodes for a novel transmembrane glycoprotein. In situ
hybridization and RT-PCR analysis revealed that Tmem10
is selectively expressed by oligodendrocytes and that its
expression is induced during their differentiation. Developmental
immunofluorescence analysis demonstrated that
Tmem10 starts to be expressed in the white matter tracks
of the cerebellum and the corpus callosum at the onset of
myelination after the appearance of other myelin genes
such as MBP. In contrast to the spinal cord and brain,
Tmem10 was not detected in myelinating Schwann cells,
indicating that it is a CNS-specific myelin protein. In
mature oligodendrocytes, Tmem10 was present at the cell
soma and processes, as well as along myelinated internodes,
where it was occasionally concentrated at the paranodes.
In myelinating spinal cord cultures, Tmem10 was
detected in MBP-positive cellular processes that were
aligned with underlying axons before myelination commenced.
These results suggest a possible role of Tmem10
in oligodendrocyte differentiation and CNS myelination.This work was supported by grants from the
Dr. Miriam and Sheldon G. Adelson Medical Research
Foundation
Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome
Dendritic cells are critically involved in the promotion and regulation of Tcell responses. Here, we report a mouse strain that lacks conventional CD11chi dendritic cells (cDCs) because of constitutive cell-type specific expression of a suicide gene. As expected, cDC-less mice failed to mount effective Tcell responses resulting in impaired viral clearance. In contrast, neither thymic negative selection nor T regulatory cell generation or Tcell homeostasis were markedly affected. Unexpectedly, cDC-less mice developed a progressive myeloproliferative disorder characterized by prominent extramedullary hematopoiesis and increased serum amounts of the cytokine Flt3 ligand. Our data identify a critical role of cDCs in the control of steady-state hematopoiesis, revealing a feedback loop that links peripheral cDCs to myelogenesis through soluble growth factors, such as Flt3 ligand