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Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer’s disease mutation

Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer’s disease mutation

Summary: SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer’s disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-β (Aβ) in mouse models and AD patients, suggesting that increasing expression of this receptor could be a therapeutic option for decreasing the amount of amyloidogenic products in affected individuals. We characterize a new mouse model in which SORLA is overexpressed, and show a decrease in Aβ concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent Aβ peptides. Aβ binds to the amino-terminal VPS10P domain of SORLA, and this binding is impaired by a familial AD mutation in SORL1. Thus, loss of SORLA’s Aβ sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development.

Authors:
Caglayan S, Takagi-Niidome S, Liao F, Carlo AS, Schmidt V, Burgert T, Kitago Y, Füchtbauer EM, Füchtbauer A, Holtzman DM, Takagi J, Willnow TE.

Link:
Sci Transl Med. 2014 Feb 12;6(223):223ra20. doi: 10.1126/scitranslmed.3007747.

Triple-Quantum-Filtered Sodium Imaging at 9.4 Tesla

Mitochondrial Dynamics Controlled by Mitofusins Regulate Agrp Neuronal Activity and Diet-Induced Obesity

Abstract

PURPOSE:

Efficient acquisition of triple-quantum-filtered (TQF) sodium images at ultra-high field (UHF) strength.

METHODS:

A three-pulse preparation and a stack of double-spirals were used for the acquisition of TQF images at 9.4 Tesla. The flip angles of the TQ preparation were smoothly reduced toward the edge of k-space along the partition-encoding direction. In doing so, the specific absorption rate could be reduced while preserving the maximal signal intensity for the partitions most relevant for image contrast in the center of k-space. Simulations, phantom and in vivo measurements were used to demonstrate the usefulness of the proposed method.

RESULTS:

A higher sensitivity (∼20%) was achieved compared to the standard acquisition without flip angle apodization. Signals from free sodium ions were successfully suppressed irrespective of the amount of apodization used. B0 corrected TQF images with a nominal resolution of 5 × 5 × 5 mm3 and an acceptable signal-to-noise ratio could be acquired in vivo within 21 min.

CONCLUSION:

Conventional TQF in combination with flip angle apodization permits to exploit more efficiently the increased sensitivity available at 9.4T. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Authors:
Mirkes C, Shajan G, Bause J, Buckenmaier K, Hoffmann J, Scheffler K.

Link:
http://www.ncbi.nlm.nih.gov/pubmed/25846242

Multimodal neuroimaging in humans at 9.4 T: a technological breakthrough towards advanced metabolic imaging scanner

Multimodal neuroimaging in humans at 9.4 T

A technological breakthrough towards an advanced metabolic imaging scanner

The aim of this paper is twofold: firstly, to explore the potential of simultaneously acquiring multimodal
MR–PET–EEG data in a human 9.4 T scanner to provide a platform for metabolic brain imaging. Secondly, to demonstrate that the three modalities are complementary, with MRI providing excellent structural and functional
imaging, PET providing quantitative molecular imaging, and EEG providing superior temporal resolution.

A 9.4 TMRI scanner equipped with a PET insert and a commercially available EEG device was used to acquire in vivo proton-based images, spectra, and sodium- and oxygenbased images with MRI, EEG signals from a human subject in a static 9.4 T magnetic field, and demonstrate hybrid MR–PET capability in a rat model. High-resolution images of the in vivo human brain with an isotropic resolution of 0.5 mm and post-mortem brain images of the cerebellum with an isotropic resolution of 320 lm are presented. A 1H spectrum was also acquired from 2 9 2 9 2 mm voxel in the brain allowing 12 metabolites to be identified. Imaging based on sodium and oxygen is demonstrated with isotropic resolutions of 2 and 5 mm, respectively.

Auditory evoked potentials measured in a static field of 9.4 T are shown. Finally, hybrid MR–PET capability at 9.4 T in the human scanner is demonstrated in a rat model. Initial progress on the road to 9.4 T multimodal MR–PET–EEG is illustrated. Ultra-high resolution structural imaging, high-resolution images of the sodium distribution and proof-of-principle 17O data are clearly demonstrated. Further, simultaneous MR–PET data are presented without artefacts and EEG data successfully corrected for the cardioballistic artefact at 9.4 T are presented.

Keywords Ultra-high field MRI  MRI–PET  PET Metabolic imaging  Multimodal MR–PET–EEG

Conference Notice

Upcoming conference:
Ultrahigh Field Magnetic Resonance

5th Annual Scientific Symposium
Ultrahigh Field Magnetic Resonance: Clinical Needs, Research Promises and Technical Solutions
Friday, June 20th 2014
8.45 a.m. – 8 p.m.
Max Delbrück
Communications Center
(MDC.C), Berlin

program_5th_UHF_Symposium

Welcome Message from the Coordinators

The Helmholtz Alliance ICEMEDImaging and Curing Environmental Metabolic Diseases – is a network of synergistic excellence representing a worldwide unique research consortium of biomedical research scientists, clinicians and cutting edge metabolic imaging experts in Germany with the goal to improve our understanding of the brain in metabolic diseases. Our Alliance consists of more than 30 leading German diabetes and obesity research teams and research centers enhanced by cooperative alliances with Sanofi Aventis Pharmaceuticals and leading internationally renowned diabetes and obesity research centers at Cambridge and Yale University.

ICEMED is pursuing an ambitious goal: the overarching intent of our Alliance is to embrace the sustainable theme of finding new medicines and treatment approaches to cure obesity and type 2 Diabetes over the next five years. To that end, the alliance will focus on identifying, visualizing, dissecting and targeting central nervous system pathways (in both central control circuits and brain-periphery crosstalk) that regulate systems metabolism. This aspect of the Alliance is synergistically enhanced by the integration of comprehensive neuroimaging expertise using and further improving cutting edge, in vivo metabolic imaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI) in animal models and humans.

The Alliance has chosen an innovative strategy with an interdisciplinary team – leading the way for personalized therapy. Our Alliance connects multi-disciplinary basic research with clinical application. We believe that together we can succeed in stemming the spreading pandemic of diabetes and obesity and hopefully reverse it. With translation being the central perspective of this Alliance, ICEMED has also assembled clinical and pharmacological experience, including several university hospital directors with leading reputation in the field of metabolic research (Prof. H.-U. Häring, Prof. J. Spranger, Prof. J. Brüning, Prof. H. Lehnert, Prof. M. Stumvoll). This ensures the efficient implementation of scientific insights in everyday medical practice.
Finally, we are extremely fortunate, to have the unique opportunity to work as physicians, pharmacologists, and biologists side by side with outstanding physicists led by our ICEMED co-coordinator, Professor Jon Shah (Helmholtz Forschungszentrum Jülich), who in recent years has developed new technologies for the simultaneous imaging of multiple metabolic processes in the human brain. Almost all leading German ultra-high field MRI institutions are part of this Alliance and contribute a huge amount of unrivalled expertise.
The unique ICEMED Alliance is thus perfectly positioned to lead the way for alliances for metabolic research throughout the world: national science resources are used synergistically and can thus be implemented in personalized, effective treatment strategies. We invite our neuroscience, imaging, and metabolism research colleagues from around the world to contact us in order to overcome one of the preeminent challenges of our time together: the metabolic syndrome epidemic.


The orphan receptor Gpr83

The orphan receptor Gpr83 regulates systemic energy metabolism
via 
ghrelin-dependent and ghrelin-independent mechanisms

The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti- related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyper- phagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways.

The murine G protein-coupled receptor (GPCR) 83 (Gpr83) is an orphan receptor belonging to the rhodopsin-like or testis, as well as the white and brown adipose tissue (Fig. 1a). Of appreciable note, analysis of hypothalamic Gpr83 expression revealed a decrease in mice with diet-induced obesity as compared with age-matched, lean controls (Fig. 1b). Further- more, fasting of lean mice for 12, 24 or 36 h resulted in a time- dependent decrease in the hypothalamic expression of Gpr83 (Fig. 1c). Refeeding with either a HFD or a fat-free diet for 6 h caused a subsequent increase in hypothalamic Gpr83 mRNA expression (Fig. 1c). In situ hybridization histochemistry in combination with immunohistochemistry revealed a broad abundance of Gpr83 in the ARC. In particular, we found Gpr83 expressed in specific subsets of ARC neurons that express Ghsr1a (Fig. 2a–c) and AgRP (Fig. 2d,f).
Heterodimerization of Gpr83 and Ghsr1a. To determine whether Gpr83 influences ghrelin–Ghsr1a signalling, we next examined whether both receptors interact in vitro. Both sandwich enzyme-linked immunosorbent assay (ELISA) and a yellow fluorescent protein (YFP)-based protein complementation assay (YFP-PCA) revealed heterodimerization of Gpr83 and Ghsr1a (Fig. 3a,b). Furthermore, cotransfection of Ghsr1a and Gpr83 in HEK293 cells led to a 43% reduction in ghrelin-stimulated Ghsr1a activity compared with control cells cotransfected with Ghsr1a and the rat muscarinic acetylcholine receptor M3 (rM3R) (Fig. 3c). Of appreciable note, this effect was not due to changes in the cell surface or total Ghsr1a expression (Fig. 3d,e), and Gpr83 activity was not influenced by treatment with acyl ghrelin, des-acyl ghrelin or obestatin (Supplementary Fig. S1A). Furthermore, heterodimerization of Gpr83 and Ghsr1a was also observed in mouse hypothalamic N41 cells cotransfected with Ghsr1a and Gpr83 (Supplementary Fig. S1B). Together, these data indicate that Gpr83–Ghsr1a heterodimerization reduces activation of Ghsr1a by ghrelin, thus supporting a possible role for Gpr83 in the regulation of energy homeostasis by reducing the ability of ghrelin to activate its only known endogenous receptor.
Metabolic phenotype of chow-fed Gpr83 ko mice. To determine whether Gpr83 has a role in regulating systemic metabolism in vivo, we next assessed the metabolic phenotype of Gpr83- deficient (Gpr83 ko) mice. These mice had normal body weight, food intake, glucose tolerance and insulin sensitivity when fed a regular chow diet (Fig. 4), whereas free-fatty acids (FFA) were increased under the same conditions (Table 1). Compared with wild-type (wt) control mice, body fat mass (Fig. 4b) and plasma leptin levels (Table 1) were moderately decreased without any1 family A of GPCRs . This family is by far the largest subfamily of GPCRs and includes several receptors implicated in the regulation of systemic metabolism, such as the ghrelin receptor (Ghsr1a)2,3 and the orexin receptors 1 and 2 (Ox1r and Ox2r)4. Gpr83 was originally identified as a glucocorticoid- induced transcript in a murine T cell line and, therefore, was referred to as glucocorticoid-induced receptor5. Induction of Gpr83 mRNA expression following dexamethasone6 or amphetamine7 treatment suggests a possible role in the regu- lation of the hypothalamus–pituitary–adrenal axis. This possibility is further supported by the observation that Gpr83 is expressed in hypothalamic nuclei that govern energy balance, such as the arcuate nucleus (ARC), the paraventricular nucleus and the lateral hypothalamic area6,8–10. As Gpr83 is expressed in hypothalamic nuclei relevant for energy metabolism control and as a potential modulator of the hypothalamus–pituitary–adrenal axis might also be relevant for systems metabolism, we hypothesized that Gpr83 might have a role in the central regulation of energy metabolism.
To test this hypothesis, we analysed the expression of Gpr83 in the mouse hypothalamus and observed that its expression is regulated by nutrient availability. In the ARC, we further find Gpr83 being colocalized with both the ghrelin receptor (Ghsr1a) and the agouti-related protein (AgRP), and in vitro analysis in HEK293 and mouse hypothalamic N41 cells show hetero- dimerization of Gpr83 with Ghsr1a that reduces ghrelin receptor activity. In line with this observation, the effects of ghrelin treatment on food intake and adiposity are enhanced in Gpr83 knock-out (Gpr83 ko) mice, thus supporting a functional interaction between Gpr83 and Ghsr1a in vivo. However, Gpr83 ko mice are also protected from obesity and glucose intolerance following exposure to high-fat diet (HFD), despite relative hyperphagia and increased hypothalamic expression of AgRP, Npy, Hcrt and Ghsr1a. Taken together, these data suggest that Gpr83 has multiple ghrelin-dependent and ghrelin-independent roles in the regulation of systemic energy metabolism.

ARTICLE

Received 30 Oct 2012,
Accepted 2 May 2013,
Published 7 Jun 2013

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The Authors

Timo D. Mu ̈ller1,*, Anne Mu ̈ller2,*, Chun-Xia Yi1,*, Kirk M. Habegger3, Carola W. Meyer1, Bruce D. Gaylinn4, Brian Finan1, Kristy Heppner3, Chitrang Trivedi3, Maximilian Bielohuby5, William Abplanalp3, Franziska Meyer2, Carolin L. Piechowski2, Juliane Pratzka2, Kerstin Stemmer1, Jenna Holland3, Jazzmin Hembree3, Nakul Bhardwaj3, Christine Raver3, Nickki Ottaway3, Radha Krishna3, Renu Sah6, Floyd R. Sallee6, Stephen C. Woods7, Diego Perez-Tilve3, Martin Bidlingmaier5, Michael O. Thorner4, Heiko Krude2, David Smiley8, Richard DiMarchi8, Susanna Hofmann9, Paul T. Pfluger1,3, Gunnar Kleinau2, Heike Biebermann2 & Matthias H. Tscho ̈p1,3

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