Inflammation, neurodegeneration and protein aggregation in the retina as ocular biomarkers for Alzheimer’s Disease in the 3xTg-AD mouse model

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the pathogenesis of AD a pivotal role is played by two neurotoxic proteins that aggregate and accumulate in the central nervous system: amyloid beta and hyper-phosphorylated tau. Accumulation of extracellular amyloid beta plaques and intracellular hyper-phosphorylated tau tangles, and consequent neuronal loss begins 10-15 years before any cognitive impairment. In addition to cognitive and behavioral deficits, sensorial abnormalities have been described in AD patients and in some AD transgenic mouse models. Retina can be considered a simple model of the brain, as some pathological changes and therapeutic strategies from the brain may be observed or applicable to the retina. Here we propose new retinal biomarkers that could anticipate the AD diagnosis and help the beginning and the follow-up of possible future treatments. We analyzed retinal tissue of triple-transgenic AD mouse model (3xTg-AD) for the presence of pathological hallmarks during disease progression. We found the presence of amyloid beta plaques, tau tangles, neurodegeneration, and astrogliosis in the retinal ganglion cell layer of 3xTg-AD mice, already at pre-symptomatic stage. Moreover, retinal microglia in pre-symptomatic mice showed a ramified, anti-inflammatory phenotype which, during disease progression, switches to a pro-inflammatory, less ramified one, becoming neurotoxic. We hypothesize retina as a window through which monitor AD-related neurodegeneration process

Chemokine fractalkine/CX3CL1 negatively modulates active glutamatergic synapses in rat hippocampal neurons

We examined the effects of the chemokine fractalkine (CX3CL1) on EPSCs evoked by electrical stimulation of Schaffer collaterals in patch-clamped CA1 pyramidal neurons from rat hippocampal slices. Acute application of CX3CL1 caused a sustained reduction of EPSC amplitude, with partial recovery after washout. CX3CL1-induced EPSC depression is postsynaptic in nature, because paired-pulse ratio was maintained, amplitude distribution of spontaneous excitatory postsynaptic currents shifted to lower values, and whole-cell current responses to AMPA were reversibly inhibited. EPSC depression by CX3CL1 is mediated by CX3CL1 receptor (CX3CR1), because CX3CL1 was unable to influence EPSC amplitude in CA1 pyramidal neurons from CX3CR1 knock-out mice. CX3CL1-induced depression of both EPSC and AMPA current was not observed in the absence of afferent fiber stimulation or AMPA receptor activation, respectively, indicating the requirement of sustained receptor activity for its development. Findings obtained from hippocampal slices, cultured hippocampal neurons, and transfected human embryonic kidney cells indicate that a Ca2+-, cAMP-, and phosphatase-dependent process is likely to modulate CX3CL1 effects because of the following: (1) CX3CL1-induced depression was antagonized by intracellular BAPTA, 8Br-cAMP, phosphatase inhibitors, and pertussis toxin (PTX); (2) CX3CL1 inhibited forskolin-induced cAMP formation sensitive to PTX; and (3) CX3CL1 inhibited forskolin-induced Ser845 GluR1 phosphorylation, which was sensitive to PTX and dependent on Ca2+ and phosphatase activity. Together, these findings indicate that CX3CL1 negatively modulates AMPA receptor function at active glutamatergic synapses through cell-signaling pathways by influencing the balance between kinase and phosphatase activity

KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages

Among the strategies adopted by glioma to successfully invade the brain parenchyma is turning the infiltrating microglia/macrophages (M/MΦ) into allies, by shifting them toward an anti-inflammatory, pro-tumor phenotype. Both glioma and infiltrating M/MΦ cells express the Ca(2+)-activated K(+) channel (KCa3.1), and the inhibition of KCa3.1 activity on glioma cells reduces tumor infiltration in the healthy brain parenchyma. We wondered whether KCa3.1 inhibition could prevent the acquisition of a pro-tumor phenotype by M/MΦ cells, thus contributing to reduce glioma development. With this aim, we studied microglia cultured in glioma-conditioned medium or treated with IL-4, as well as M/MΦ cells acutely isolated from glioma-bearing mice and from human glioma biopsies. Under these different conditions, M/MΦ were always polarized toward an anti-inflammatory state, and preventing KCa3.1 activation by 1-[(2-Chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), we observed a switch toward a pro-inflammatory, antitumor phenotype. We identified FAK and PI3K/AKT as the molecular mechanisms involved in this phenotype switch, activated in sequence after KCa3.1. Anti-inflammatory M/MΦ have higher expression levels of KCa3.1 mRNA (kcnn4) that are reduced by KCa3.1 inhibition. In line with these findings, TRAM-34 treatment, in vivo, significantly reduced the size of tumors in glioma-bearing mice. Our data indicate that KCa3.1 channels are involved in the inhibitory effects exerted by the glioma microenvironment on infiltrating M/MΦ, suggesting a possible role as therapeutic targets in glioma

Cosmic dance in the Shapley Concentration Core - I. A study of the radio emission of the BCGs and tailed radio galaxies

The Shapley Concentration ($z\approx0.048$) covers several degrees in the Southern Hemisphere, and includes galaxy clusters in advanced evolutionary stage, groups of clusters in the early stages of merger, fairly massive clusters with ongoing accretion activity, and smaller groups located in filaments in the regions between the main clusters. With the goal to investigate the role of cluster mergers and accretion on the radio galaxy population, we performed a multi-wavelength study of the BCGs and of the galaxies showing extended radio emission in the cluster complexes of Abell 3528 and Abell 3558. Our study is based on a sample of 12 galaxies. We observed the clusters with the GMRT at 235, 325 and 610 MHz, and with the VLA at 8.46 GHz. We complemented our study with the TGSS at 150 MHz, the SUMSS at 843 MHz and ATCA at 1380, 1400, 2380, and 4790 MHz data. Optical imaging with ESO-VST and mid-IR coverage with WISE are also available for the host galaxies. We found deep differences in the properties of the radio emission of the BCGs in the two cluster complexes. The BCGs in the A3528 complex and in A3556, which are relaxed cool-core objects, are powerful active radio galaxies. They also present hints of restarted activity. On the contrary, the BCGs in A3558 and A3562, which are well known merging systems, are very faint, or quiet, in the radio band. The optical and IR properties of the galaxies are fairly similar in the two complexes, showing all passive red galaxies. Our study shows remarkable differences in the radio properties of the BGCs, which we relate to the different dynamical state of the host cluster. On the contrary, the lack of changes between such different environments in the optical band suggests that the dynamical state of galaxy clusters does not affect the optical counterparts of the radio galaxies, at least over the life-time of the radio emission.Comment: 24 pages, 11 figures, accepted for publication in Astronomy & Astrophysic

Shapley Supercluster Survey: Construction of the photometric catalogues and i-band data release

The Shapley Supercluster Survey is a multi-wavelength survey covering an area of ∼23 deg² (∼260 Mpc² at z = 0.048) around the supercluster core, including nine Abell and two poor clusters, having redshifts in the range 0.045–0.050. The survey aims to investigate the role of the cluster-scale mass assembly on the evolution of galaxies, mapping the effects of the environment from the cores of the clusters to their outskirts and along the filaments. The optical (ugri) imaging acquired with OmegaCAM on the VLT Survey Telescope is essential to achieve the project goals providing accurate multi-band photometry for the galaxy population down to m∗ + 6. We describe the methodology adopted to construct the optical catalogues and to separate extended and point-like sources. The catalogues reach average 5σ limiting magnitudes within a 3 arcsec diameter aperture of ugri = [24.4,24.6,24.1,23.3] and are 93 per cent complete down to ugri = [23.8,23.8,23.5,22.0] mag, corresponding to ∼m∗ r + 8.5. The data are highly uniform in terms of observing conditions and all acquired with seeing less than 1.1 arcsec full width at half-maximum. The median seeing in r band is 0.6 arcsec, corresponding to 0.56 kpc h⁻¹ 70 at z = 0.048. While the observations in the u, g and r bands are still ongoing, the i-band observations have been completed, and we present the i-band catalogue over the whole survey area. The latter is released and it will be regularly updated, through the use of the Virtual Observatory tools. This includes 734 319 sources down to i = 22.0 mag and it is the first optical homogeneous catalogue at such a depth, covering the central region of the Shapley supercluster

Shapley Supercluster Survey (ShaSS): Galaxy Evolution from Filaments to Cluster Cores

We present an overview of a multi-wavelength survey of the Shapley supercluster (SSC; z~0.05) covering a contiguous area of 260 h^-2_70 Mpc^2 including the supercluster core. The project main aim is to quantify the influence of cluster-scale mass assembly on galaxy evolution in one of the most massive structures in the local Universe. The Shapley supercluster survey (ShaSS) includes nine Abell clusters (A3552, A3554, A3556, A3558, A3559, A3560, A3562, AS0724, AS0726) and two poor clusters (SC1327- 312, SC1329-313) showing evidence of cluster-cluster interactions. Optical (ugri) and near-infrared (K) imaging acquired with VST and VISTA allow us to study the galaxy population down to m*+6 at the supercluster redshift. A dedicated spectroscopic survey with AAOmega on the Anglo-Australian Telescope provides a magnitude-limited sample of supercluster members with 80% completeness at ~m*+3. We derive the galaxy density across the whole area, demonstrating that all structures within this area are embedded in a single network of clusters, groups and filaments. The stellar mass density in the core of the SSC is always higher than 9E09 M_sun Mpc^-3, which is ~40x the cosmic stellar mass density for galaxies in the local Universe. We find a new filamentary structure (~7 Mpc long in projection) connecting the SSC core to the cluster A3559, as well as previously unidentified density peaks. We perform a weak-lensing analysis of the central 1 sqdeg field of the survey obtaining for the central cluster A3558 a mass of M_500=7.63E14 M_sun, in agreement with X-ray based estimates.Comment: 22 pages, 11 figures. Accepted for publication on MNRA

The Fornax Deep Survey with VST. I. The extended and diffuse stellar halo of NGC~1399 out to 192 kpc

[Abrigded] We have started a new deep, multi-imaging survey of the Fornax cluster, dubbed Fornax Deep Survey (FDS), at the VLT Survey Telescope. In this paper we present the deep photometry inside two square degrees around the bright galaxy NGC1399 in the core of the cluster. We found a very extended and diffuse envelope surrounding the luminous galaxy NGC1399: we map the surface brightness out to 33 arcmin (~ 192 kpc) from the galaxy center and down to about 31 mag/arcsec^2 in the g band. The deep photometry allows us to detect a faint stellar bridge in the intracluster region between NGC1399 and NGC1387. By analyzing the integrated colors of this feature, we argue that it could be due to the ongoing interaction between the two galaxies, where the outer envelope of NGC1387 on its east side is stripped away. By fitting the light profile, we found that it exists a physical break radius in the total light distribution at R=10 arcmin (~58 kpc) that sets the transition region between the bright central galaxy and the outer exponential stellar halo. We discuss the main implications of this work on the build-up of the stellar halo at the center of the Fornax cluster. By comparing with the numerical simulations of the stellar halo formation for the most massive BCGs, we find that the observed stellar halo mass fraction is consistent with a halo formed through the multiple accretion of progenitors with a stellar mass in the range 10^8 - 10^11 M_sun. This might suggest that the halo of NGC1399 has also gone through a major merging event. The absence of a significant number of luminous stellar streams and tidal tails out to 192 kpc suggests that the epoch of this strong interaction goes back to an early formation epoch. Therefore, differently from the Virgo cluster, the extended stellar halo around NGC1399 is characterised by a more diffuse and well-mixed component, including the ICL.Comment: Accepted for publication in ApJ; 25 pages and 14 figures. An higher resolution file is available at the following link https://www.dropbox.com/s/fvltppduysdn6pb/NGC1399_fin_2c.pdf?dl=

Bromodomain and extraterminal domain (BET) protein inhibition hinders glioblastoma progression by inducing autophagy-dependent differentiation

Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant primary brain tumor, and it is characterized by a high recurrence incidence and poor prognosis due to the presence of a highly heterogeneous mass of stem cells with self-renewal capacity and stemness maintenance ability. In recent years, the epigenetic landscape of GBM has been explored and many epigenetic alterations have been investigated. Among the investigated epigenetic abnormalities, the bromodomain and extra-terminal domain (BET) chromatin readers have been found to be significantly overexpressed in GBM. In this work, we investigated the effects of BET protein inhibition on GBM cell reprogramming. We found that the pan-BET pharmacological inhibitor JQ1 was able to promote a differentiation program in GBM cells, thus impairing cell proliferation and enhancing the toxicity of the drug Temozolomide (TMZ). Notably, the pro-differentiation capability of JQ1 was prevented in autophagy-defective models, suggesting that autophagy activation is necessary for BET protein activity in regulating glioma cell fate. Given the growing interest in epigenetic therapy, our results further support the possibility of introducing a BET-based approach in GBM clinical management