Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons.

Disrupting particular mitochondrial fission and fusion proteins leads to the death of specific neuronal populations; however, the normal functions of mitochondrial fission in neurons are poorly understood, especially in vivo, which limits the understanding of mitochondrial changes in disease. Altered activity of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) may contribute to the pathophysiology of several neurologic diseases. To study Drp1 in a neuronal population affected by Alzheimer's disease (AD), stroke, and seizure disorders, we postnatally deleted Drp1 from CA1 and other forebrain neurons in mice (CamKII-Cre, Drp1lox/lox (Drp1cKO)). Although most CA1 neurons survived for more than 1 year, their synaptic transmission was impaired, and Drp1cKO mice had impaired memory. In Drp1cKO cell bodies, we observed marked mitochondrial swelling but no change in the number of mitochondria in individual synaptic terminals. Using ATP FRET sensors, we found that cultured neurons lacking Drp1 (Drp1KO) could not maintain normal levels of mitochondrial-derived ATP when energy consumption was increased by neural activity. These deficits occurred specifically at the nerve terminal, but not the cell body, and were sufficient to impair synaptic vesicle cycling. Although Drp1KO increased the distance between axonal mitochondria, mitochondrial-derived ATP still decreased similarly in Drp1KO boutons with and without mitochondria. This indicates that mitochondrial-derived ATP is rapidly dispersed in Drp1KO axons, and that the deficits in axonal bioenergetics and function are not caused by regional energy gradients. Instead, loss of Drp1 compromises the intrinsic bioenergetic function of axonal mitochondria, thus revealing a mechanism by which disrupting mitochondrial dynamics can cause dysfunction of axons

Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease.

The maintenance of genomic integrity is essential for normal cellular functions. However, it is difficult to maintain over a lifetime in postmitotic cells such as neurons, in which DNA damage increases with age and is exacerbated by multiple neurological disorders, including Alzheimer's disease (AD). Here we used immunohistochemical staining to detect DNA double strand breaks (DSBs), the most severe form of DNA damage, in postmortem brain tissues from patients with mild cognitive impairment (MCI) or AD and from cognitively unimpaired controls. Immunostaining for γH2AX-a post-translational histone modification that is widely used as a marker of DSBs-revealed increased proportions of γH2AX-labeled neurons and astrocytes in the hippocampus and frontal cortex of MCI and AD patients, as compared to age-matched controls. In contrast to the focal pattern associated with DSBs, some neurons and glia in humans and mice showed diffuse pan-nuclear patterns of γH2AX immunoreactivity. In mouse brains and primary neuronal cultures, such pan-nuclear γH2AX labeling could be elicited by increasing neuronal activity. To assess whether pan-nuclear γH2AX represents DSBs, we used a recently developed technology, DNA damage in situ ligation followed by proximity ligation assay, to detect close associations between γH2AX sites and free DSB ends. This assay revealed no evidence of DSBs in neurons or astrocytes with prominent pan-nuclear γH2AX labeling. These findings suggest that focal, but not pan-nuclear, increases in γH2AX immunoreactivity are associated with DSBs in brain tissue and that these distinct patterns of γH2AX formation may have different causes and consequences. We conclude that AD is associated with an accumulation of DSBs in vulnerable neuronal and glial cell populations from early stages onward. Because of the severe adverse effects this type of DNA damage can have on gene expression, chromatin stability and cellular functions, DSBs could be an important causal driver of neurodegeneration and cognitive decline in this disease

The AGASA/SUGAR Anisotropies and TeV Gamma Rays from the Galactic Center: A Possible Signature of Extremely High-energy Neutrons

Recent analysis of data sets from two extensive air shower cosmic ray detectors shows tantalizing evidence of an anisotropic overabundance of cosmic rays towards the Galactic Center (GC) that ``turns on'' around $10^{18}$ eV. We demonstrate that the anisotropy could be due to neutrons created at the Galactic Center through charge-exchange in proton-proton collisions, where the incident, high energy protons obey an $\sim E^{-2}$ power law associated with acceleration at a strong shock. We show that the normalization supplied by the gamma-ray signal from EGRET GC source 3EG J1746-2851 -- ascribed to pp induced neutral pion decay at GeV energies -- together with a very reasonable spectral index of 2.2, predicts a neutron flux at $\sim 10^{18}$ eV fully consistent with the extremely high energy cosmic ray data. Likewise, the normalization supplied by the very recent GC data from the HESS air-Cerenkov telescope at \~TeV energies is almost equally-well compatible with the $\sim 10^{18}$ eV cosmic ray data. Interestingly, however, the EGRET and HESS data appear to be themselves incompatible. We consider the implications of this discrepancy. We discuss why the Galactic Center environment can allow diffusive shock acceleration at strong shocks up to energies approaching the ankle in the cosmic ray spectrum. Finally, we argue that the shock acceleration may be occuring in the shell of Sagittarius A East, an unusual supernova remnant located very close to the Galactic Center. If this connection between the anisotropy and Sagittarius A East could be firmly established it would be the first direct evidence for a particular Galactic source of cosmic rays up to energies near the ankle.Comment: 57 pages, 2 figure

Astrocytic gap junctional communication is reduced in amyloid-β-treated cultured astrocytes, but not in Alzheimer's disease transgenic mice

Alzheimer's disease is characterized by accumulation of amyloid deposits in brain, progressive cognitive deficits and reduced glucose utilization. Many consequences of the disease are attributed to neuronal dysfunction, but roles of astrocytes in its pathogenesis are not well understood. Astrocytes are extensively coupled via gap junctions, and abnormal trafficking of metabolites and signalling molecules within astrocytic syncytia could alter functional interactions among cells comprising the neurovascular unit. To evaluate the influence of amyloid-β on astrocyte gap junctional communication, cultured astrocytes were treated with monomerized amyloid-β1–40 (1 μmol/l) for intervals ranging from 2 h to 5 days, and the areas labelled by test compounds were determined by impaling a single astrocyte with a micropipette and diffusion of material into coupled cells. Amyloid-β-treated astrocytes had rapid, sustained 50–70% reductions in the area labelled by Lucifer Yellow, anionic Alexa Fluor® dyes and energy-related compounds, 6-NBDG (a fluorescent glucose analogue), NADH and NADPH. Amyloid-β treatment also caused a transient increase in oxidative stress. In striking contrast with these results, spreading of Lucifer Yellow within astrocytic networks in brain slices from three regions of 8.5–14-month-old control and transgenic Alzheimer's model mice was variable, labelling 10–2000 cells; there were no statistically significant differences in the number of dye-labelled cells among the groups or with age. Thus amyloid-induced dysfunction of gap junctional communication in cultured astrocytes does not reflect the maintenance of dye transfer through astrocytic syncytial networks in transgenic mice; the pathophysiology of Alzheimer's disease is not appropriately represented by the cell culture system

EGRET Observations of the Extragalactic Gamma Ray Emission

The all-sky survey in high-energy gamma rays (E$>$30 MeV) carried out by the Energetic Gamma Ray Experiment Telescope (EGRET) aboard the Compton Gamma-Ray Observatory provides a unique opportunity to examine in detail the diffuse gamma-ray emission. The observed diffuse emission has a Galactic component arising from cosmic-ray interactions with the local interstellar gas and radiation as well an almost uniformly distributed component that is generally believed to originate outside the Galaxy. Through a careful study and removal of the Galactic diffuse emission, the flux, spectrum and uniformity of the extragalactic emission is deduced. The analysis indicates that the extragalactic emission is well described by a power law photon spectrum with an index of -(2.10+-0.03) in the 30 MeV to 100 GeV energy range. No large scale spatial anisotropy or changes in the energy spectrum are observed in the deduced extragalactic emission. The most likely explanation for the origin of this extragalactic high-energy gamma-ray emission is that it arises primarily from unresolved gamma-ray-emitting blazars.Comment: 19 pages latex, 10 figures, accepted for publication in Ap

EGRET Spectral Index and the Low-Energy Peak Position in the Spectral Energy Distribution of EGRET-Detected Blazars

In current theoretical models of the blazar subclass of active galaxies, the broadband emission consists of two components: a low-frequency synchrotron component with a peak in the IR to X-ray band, and a high-frequency inverse Compton component with a peak in the gamma-ray band. In such models, the gamma-ray spectral index should be correlated with the location of the low-energy peak, with flatter gamma-ray spectra expected for blazars with synchrotron peaks at higher photon energies and vice versa. Using the EGRET-detected blazars as a sample, we examine this correlation and possible uncertainties in its construction.Comment: 17 pages including 1 figure, accepted for publication in The Astrophysical Journa

Data on 824 fireballs observed by the digital cameras of the European Fireball Network in 2017-2018. I. Description of the network, data reduction procedures, and the catalog

A catalog of 824 fireballs (bright meteors), observed by a dedicated network of all-sky digital photographic cameras in central Europe in the years 2017-2018 is presented. The status of the European Fireball Network, established in 1963, is described. The cameras collect digital images of meteors brighter than an absolute magnitude of about -2 and radiometric light curves with a high temporal resolution of those brighter than a magnitude ~ -4. All meteoroids larger than 5 grams, corresponding to sizes of about 2 cm, are detected regardless of their entry velocity. High-velocity meteoroids are detected down to masses of about 0.1 gram. The largest observed meteoroid in the reported period 2017-2018 had a mass of about 100 kg and a size of about 40 cm. The methods of data analysis are explained and all catalog entries are described in detail. The provided data include the fireball date and time, atmospheric trajectory and velocity, the radiant in various coordinate systems, heliocentric orbital elements, maximum brightness, radiated energy, initial and terminal masses, maximum encountered dynamic pressure, physical classification, and possible shower membership. Basic information on the fireball spectrum is available for some bright fireballs (apparent magnitude < -7). A simple statistical evaluation of the whole sample is provided. The scientific analysis is presented in an accompanying paper.Comment: accepted in Astronomy and Astrophysic