TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies

Measurement of Jet Shapes in Photoproduction at HERA

The shape of jets produced in quasi-real photon-proton collisions at centre-of-mass energies in the range $134-277$ GeV has been measured using the hadronic energy flow. The measurement was done with the ZEUS detector at HERA. Jets are identified using a cone algorithm in the $\eta - \phi$ plane with a cone radius of one unit. Measured jet shapes both in inclusive jet and dijet production with transverse energies $E^{jet}_T>14$ GeV are presented. The jet shape broadens as the jet pseudorapidity ($\eta^{jet}$) increases and narrows as $E^{jet}_T$ increases. In dijet photoproduction, the jet shapes have been measured separately for samples dominated by resolved and by direct processes. Leading-logarithm parton-shower Monte Carlo calculations of resolved and direct processes describe well the measured jet shapes except for the inclusive production of jets with high $\eta^{jet}$ and low $E^{jet}_T$. The observed broadening of the jet shape as $\eta^{jet}$ increases is consistent with the predicted increase in the fraction of final state gluon jets.Comment: 29 pages including 9 figure

Mitochondrial Ca2+ Overload Underlies Aβ Oligomers Neurotoxicity Providing an Unexpected Mechanism of Neuroprotection by NSAIDs

Dysregulation of intracellular Ca2+ homeostasis may underlie amyloid β peptide (Aβ) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Aβ1–42 oligomers, the assembly state correlating best with cognitive decline in AD, but not Aβ fibrils, induce a massive entry of Ca2+ in neurons and promote mitochondrial Ca2+ overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Aβ oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca2+ overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca2+ overload, cytochrome c release and cell death induced by Aβ oligomers. Our results indicate that i) mitochondrial Ca2+ overload underlies the neurotoxicity induced by Aβ oligomers and ii) inhibition of mitochondrial Ca2+ overload provides a novel mechanism of neuroprotection by NSAIDs against Aβ oligomers and AD

Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta

Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPα) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer’s disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Aβ) at the expense of sAPPα and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Aβ and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or Aβ on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not Aβ, profoundly decreased respiration and enhanced glycolysis, while mitochondrial DNA (mtDNA) transcripts were decreased, without detrimental effects to cell growth. These effects cannot be ascribed to Aβ toxicity, since higher levels of endogenous Aβ in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of β-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where APP is overexpressed, and a potential role of sAPPα or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism

Mitochondrial Superoxide Contributes to Blood Flow and Axonal Transport Deficits in the Tg2576 Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive decline in cognitive functions and the deposition of aggregated amyloid beta (Abeta) into senile plaques and the protein tau into tangles. In addition, a general state of oxidation has long been known to be a major hallmark of the disease. What is not known however, are the mechanisms by which oxidative stress contributes to the pathology of AD.In the current study, we used a mouse model of AD and genetically boosted its ability to quench free radicals of specific mitochondrial origin. We found that such manipulation conferred to the AD mice protection against vascular as well as neuronal deficits that typically affect them. We also found that the vascular deficits are improved via antioxidant modulation of the endothelial nitric oxide synthase, an enzyme primarily responsible for the production of nitric oxide, while neuronal deficits are improved via modulation of the phosphorylation status of the protein tau, which is a neuronal cytoskeletal stabilizer.These findings directly link free radicals of specific mitochondrial origin to AD-associated vascular and neuronal pathology

Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

The identification of early mechanisms underlying Alzheimer's Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics.We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models demonstrated a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brains of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans.Mutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD

Search for magnetic monopoles with ten years of the ANTARES neutrino telescope

This work presents a new search for magnetic monopoles using data taken with the ANTARES neutrino telescope over a period of 10 years (January 2008 to December 2017). Compared to previous ANTARES searches, this analysis uses a run-by-run simulation strategy, with a larger exposure as well as a new simulation of magnetic monopoles taking into account the Kasama, Yang and Goldhaber model for their interaction cross-section with matter. No signal compatible with the passage of relativistic magnetic monopoles is observed, and upper limits on the flux of magnetic monopoles with β=v/c≥0.55, are presented. For ultra-relativistic magnetic monopoles the flux limit is ∼7×10−18 cm−2s−1sr−1

ANTARES search for point-sources of neutrinos using astrophysical catalogs: a likelihood stacking analysis

A search for astrophysical point-like neutrino sources using the data collected by the ANTARES detector between January 29, 2007 and December 31, 2017 is presented. A likelihood stacking method is used to assess the significance of an excess of muon neutrinos inducing track-like events in correlation with the location of a list of possible sources. Different sets of objects are tested in the analysis: a) a sub-sample of the \textit{Fermi} 3LAC catalog of blazars, b) a jet-obscured AGN population, c) a sample of soft gamma-ray selected radio galaxies, d) a star-forming galaxy catalog , and e) a public sample of 56 very-high-energy track events from the IceCube experiment. None of the tested sources shows a significant association with the sample of neutrinos detected by ANTARES. The smallest p-value is obtained for the radio galaxies catalog with an equal weights hypothesis, with a pre-trial p-value equivalent to a $2.8 \, \sigma$ excess, equivalent to $1.6 \, \sigma$ post-trial. In addition, the results of a dedicated analysis for the blazar MG3 J225517+2409 are also reported: this source is found to be the most significant within the \textit{Fermi} 3LAC sample, with 5 ANTARES events located at less than one degree from the source. This blazar showed evidence of flaring activity in \textit{Fermi} data, in space-time coincidence with a high-energy track detected by IceCube. An \emph{a posteriori} significance of $2.0\, \sigma$ for the combination of ANTARES and IceCube data is reported

Observation of the cosmic ray shadow of the Sun with the ANTARES neutrino telescope

[EN] The ANTARES detector is an undersea neutrino telescope in the Mediterranean Sea. The search for pointlike neutrino sources is one of the main goals of the ANTARES telescope, requiring a reliable method to evaluate the detector angular resolution and pointing accuracy. This work describes the study of the Sun ¿shadow¿ effect with the ANTARES detector. The shadow is the deficit in the atmospheric muon flux in the direction of the Sun caused by the absorption of the primary cosmic rays. This analysis is based on the data collected between 2008 and 2017 by the ANTARES telescope. The observed statistical significance of the Sun shadow detection is 3.7¿, with an estimated angular resolution of 0.59° +- 0.10°for downward-going muons. The pointing accuracy is found to be consistent with the expectations and no evidence of systematic pointing shifts is observed.The authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique, Commissariat `a l'' energie atomique et aux energies alternatives, Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France, LabEx UnivEarthS (ANR-10-LABX-0023 and ANR-18-IDEX-0001), R ' egion Ile-de-France (DIM-ACAV), Region Alsace (contract CPER), Region Provence-Alpes-Cote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fur Bildung und Forschung, Germany; Istituto Nazionale di Fisica Nucleare, Italy; Nederlandse organisatie voor Wetenschappelijk Onderzoek, the Netherlands; Council of the President of the Russian Federation for Young Scientists and Leading Scientific Schools supporting grants, Russia; Executive Unit for Financing Higher Education, Research, Development and Innovation (UEFISCDI), Romania; Ministerio de Ciencia, Innovacion, Investigacion y Universidades (MCIU): Programa Estatal de Generacion de Conocimiento (refs. PGC2018-096663-B-C41, -A-C42, -B-C43, -B-C44) (MCIU/FEDER), Severo Ochoa Centre of Excellence and MultiDark Consolider (MCIU), Junta de Andalucia (refs. SOMM17/6104/UGR and A-FQM-053-UGR18), Generalitat Valenciana: Grisolia (ref. GRISOLIA/2018/119), Spain; Ministry of Higher Education, Scientific Research and Professional Training, Morocco. We also acknowledge the technical support of Ifremer, AIM and Foselev Marine for the sea operation and the CC-IN2P3 for the computing facilities.Albert, A.; Andre, M.; Anghinolfi, M.; Anton, G.; Ardid Ramírez, M.; Aubert, J.; Aublin, J.... (2020). Observation of the cosmic ray shadow of the Sun with the ANTARES neutrino telescope. Physical Review D: covering particles, fields, gravitation, and cosmology. 102(12):1-7. https://doi.org/10.1103/PhysRevD.102.122007S1710212Ageron, M., Aguilar, J. A., Al Samarai, I., Albert, A., Ameli, F., André, M., … Ardid, M. (2011). ANTARES: The first undersea neutrino telescope. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 656(1), 11-38. doi:10.1016/j.nima.2011.06.103Alexandreas, D. E., Allen, R. C., Berley, D., Biller, S. D., Burman, R. L., Cady, D. R., … Zhang, W. (1991). Observation of shadowing of ultrahigh-energy cosmic rays by the Moon and the Sun. Physical Review D, 43(5), 1735-1738. doi:10.1103/physrevd.43.1735Andreyev, Y. M., Zakidyshev, V. N., Karpov, S. N., & Khodov, V. N. (2002). Cosmic Research, 40(6), 559-564. doi:10.1023/a:1021553713199Borione, A., Catanese, M., Covault, C. E., Cronin, J. W., Fick, B. E., Gibbs, K. G., … van der Velde, J. C. (1994). Observation of the shadows of the Moon and Sun using 100 TeV cosmic rays. Physical Review D, 49(3), 1171-1177. doi:10.1103/physrevd.49.1171Cobb, J. H., Marshak, M. L., Allison, W. W. M., Alner, G. J., Ayres, D. S., Barrett, W. L., … Wall, D. (2000). Observation of a shadow of the Moon in the underground muon flux in the Soudan 2 detector. Physical Review D, 61(9). doi:10.1103/physrevd.61.092002Bartoli, B., Bernardini, P., Bi, X. J., Bleve, C., Bolognino, I., Branchini, P., … Cao, Z. (2012). Measurement of the cosmic ray antiproton/proton flux ratio at TeV energies with the ARGO-YBJ detector. Physical Review D, 85(2). doi:10.1103/physrevd.85.022002Abeysekara, A. U., Albert, A., Alfaro, R., Alvarez, C., Álvarez, J. D., Arceo, R., … Belmont-Moreno, E. (2018). Constraining the p¯/p ratio in TeV cosmic rays with observations of the Moon shadow by HAWC. Physical Review D, 97(10). doi:10.1103/physrevd.97.102005Adamson, P., Andreopoulos, C., Ayres, D. S., Backhouse, C., Barr, G., Barrett, W. L., … Bock, G. J. (2011). Observation in the MINOS far detector of the shadowing of cosmic rays by the sun and moon. Astroparticle Physics, 34(6), 457-466. doi:10.1016/j.astropartphys.2010.10.010Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Ansseau, I. (2019). Detection of the Temporal Variation of the Sun’s Cosmic Ray Shadow with the IceCube Detector. The Astrophysical Journal, 872(2), 133. doi:10.3847/1538-4357/aaffd1Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., … Barrios-Martít, J. (2018). The cosmic ray shadow of the Moon observed with the ANTARES neutrino telescope. The European Physical Journal C, 78(12). doi:10.1140/epjc/s10052-018-6451-3First search for neutrinos in correlation with gamma-ray bursts with the ANTARES neutrino telescope. (2013). Journal of Cosmology and Astroparticle Physics, 2013(03), 006-006. doi:10.1088/1475-7516/2013/03/006Aguilar, J. A., Al Samarai, I., Albert, A., André, M., Anghinolfi, M., Anton, G., … Astraatmadja, T. (2011). A fast algorithm for muon track reconstruction and its application to the ANTARES neutrino telescope. Astroparticle Physics, 34(9), 652-662. doi:10.1016/j.astropartphys.2011.01.003BECHERINI, Y., MARGIOTTA, A., SIOLI, M., & SPURIO, M. (2006). A parameterisation of single and multiple muons in the deep water or ice. Astroparticle Physics, 25(1), 1-13. doi:10.1016/j.astropartphys.2005.10.005Carminati, G., Bazzotti, M., Margiotta, A., & Spurio, M. (2008). Atmospheric MUons from PArametric formulas: a fast GEnerator for neutrino telescopes (MUPAGE). Computer Physics Communications, 179(12), 915-923. doi:10.1016/j.cpc.2008.07.014Yepes-Ramírez, H. (2013). Characterization of optical properties of the site of the ANTARES neutrino telescope. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 725, 203-206. doi:10.1016/j.nima.2012.11.143Fusco, L. A., & Margiotta, A. (2016). The Run-by-Run Monte Carlo simulation for the ANTARES experiment. EPJ Web of Conferences, 116, 02002. doi:10.1051/epjconf/201611602002Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., … Basa, S. (2017). First all-flavor neutrino pointlike source search with the ANTARES neutrino telescope. Physical Review D, 96(8). doi:10.1103/physrevd.96.082001Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., … Belhorma, B. (2020). ANTARES and IceCube Combined Search for Neutrino Point-like and Extended Sources in the Southern Sky. The Astrophysical Journal, 892(2), 92. doi:10.3847/1538-4357/ab7afbAdrián-Martínez, S., Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., … Basa, S. (2014). SEARCHES FOR POINT-LIKE AND EXTENDED NEUTRINO SOURCES CLOSE TO THE GALACTIC CENTER USING THE ANTARES NEUTRINO TELESCOPE. The Astrophysical Journal, 786(1), L5. doi:10.1088/2041-8205/786/1/l

Search for Gamma-Ray and Neutrino Coincidences Using HAWC and ANTARES Data

In the quest for high-energy neutrino sources, the Astrophysical Multimessenger Observatory Network (AMON) has implemented a new search by combining data from the High Altitude Water Cherenkov (HAWC) observatory and the Astronomy with a Neutrino Telescope and Abyss environmental RESearch (ANTARES) neutrino telescope. Using the same analysis strategy as in a previous detector combination of HAWC and IceCube data, we perform a search for coincidences in HAWC and ANTARES events that are below the threshold for sending public alerts in each individual detector. Data were collected between July 2015 and February 2020 with a livetime of 4.39 years. Over this time period, 3 coincident events with an estimated false-alarm rate of $< 1$ coincidence per year were found. This number is consistent with background expectations.Comment: 12 pages, 5 figures, 3 table