Early Changes in Hippocampal Eph Receptors Precede the Onset of Memory Decline in Mouse Models of Alzheimer’s Disease

Abstract. Synapse loss occurs early in Alzheimer’s disease (AD) and is considered the best pathological correlate of cognitive decline. Ephrins and Eph receptors are involved in regulation of excitatory neurotransmission and play a role in cytoskeleton remodeling. We asked whether alterations in Eph receptors could underlie cognitive impairment in an AD mouse model overexpressing human amyloid-β protein precursor (hAβPP) with familial mutations (hAβPPswe-ind mice). We found that EphA4 and EphB2 receptors were reduced in the hippocampus before the development of impaired object recognition and spatial memory. Similar results were obtained in another line of transgenic AβPP mice, Tg2576. A reduction in Eph receptor levels was also found in postmortem hippocampal tissue from patients with incipient AD. At the time of onset of memory decline in hAβPPswe-ind mice, no change in surface expression of AMPA or NMDA receptor subunits was apparent, but we found changes in Eph-receptor downstream signaling, in particular a decrease in membrane-associated phospho-cofilin levels that may cause cytoskeletal changes and disrupted synaptic activity. Consistent with this finding, Eph receptor activation in cell culture increased phospho-cofilin levels. The results suggest that alterations in Eph receptors may play a role in synaptic dysfunction in the hippocampus leading to cognitive impairment in a model of AD

Overexpression of wild-type human APP in mice causes cognitive déficits and pathological features unrelated to Abeta levels

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPPwt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ42) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ- independent pathogenic pathways in Alzheimer's disease

Observation of J/ψpJ/\psi p resonances consistent with pentaquark states in Λb0→J/ψK−p{\Lambda_b^0\to J/\psi K^-p} decays

Observations of exotic structures in the $J/\psi p$ channel, that we refer to as pentaquark-charmonium states, in $\Lambda_b^0\to J/\psi K^- p$ decays are presented. The data sample corresponds to an integrated luminosity of 3/fb acquired with the LHCb detector from 7 and 8 TeV pp collisions. An amplitude analysis is performed on the three-body final-state that reproduces the two-body mass and angular distributions. To obtain a satisfactory fit of the structures seen in the $J/\psi p$ mass spectrum, it is necessary to include two Breit-Wigner amplitudes that each describe a resonant state. The significance of each of these resonances is more than 9 standard deviations. One has a mass of $4380\pm 8\pm 29$ MeV and a width of $205\pm 18\pm 86$ MeV, while the second is narrower, with a mass of $4449.8\pm 1.7\pm 2.5$ MeV and a width of $39\pm 5\pm 19$ MeV. The preferred $J^P$ assignments are of opposite parity, with one state having spin 3/2 and the other 5/2.Comment: 48 pages, 18 figures including the supplementary material, v2 after referee's comments, now 19 figure

Study of B−→DK−π+π−B^{-}\to DK^-\pi^+\pi^- and B−→Dπ−π+π−B^-\to D\pi^-\pi^+\pi^- decays and determination of the CKM angle γ\gamma

We report a study of the suppressed $B^-\to DK^-\pi^+\pi^-$ and favored $B^-\to D\pi^-\pi^+\pi^-$ decays, where the neutral $D$ meson is detected through its decays to the $K^{\mp}\pi^{\pm}$ and CP-even $K^+K^-$ and $\pi^+\pi^-$ final states. The measurement is carried out using a proton-proton collision data sample collected by the LHCb experiment, corresponding to an integrated luminosity of 3.0~fb$^{-1}$. We observe the first significant signals in the CP-even final states of the $D$ meson for both the suppressed $B^-\to DK^-\pi^+\pi^-$ and favored $B^-\to D\pi^-\pi^+\pi^-$ modes, as well as in the doubly Cabibbo-suppressed $D\to K^+\pi^-$ final state of the $B^-\to D\pi^-\pi^+\pi^-$ decay. Evidence for the ADS suppressed decay $B^{-}\to DK^-\pi^+\pi^-$, with $D\to K^+\pi^-$, is also presented. From the observed yields in the $B^-\to DK^-\pi^+\pi^-$, $B^-\to D\pi^-\pi^+\pi^-$ and their charge conjugate decay modes, we measure the value of the weak phase to be $\gamma=(74^{+20}_{-19})^{\rm o}$. This is one of the most precise single-measurement determinations of $\gamma$ to date.Comment: 22 pages, 9 figures; All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-020.htm

Measurement of the Bs0→J/ψηB_{s}^{0} \rightarrow J/\psi \eta lifetime

Using a data set corresponding to an integrated luminosity of $3 fb^{-1}$, collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of 7 and 8 TeV, the effective lifetime in the $B^0_s \rightarrow J/\psi \eta$ decay mode, $\tau_{\textrm{eff}}$, is measured to be $\tau_{\textrm{eff}} = 1.479 \pm 0.034~\textrm{(stat)} \pm 0.011 ~\textrm{(syst)}$ ps. Assuming $CP$ conservation, $\tau_{\textrm{eff}}$ corresponds to the lifetime of the light $B_s^0$ mass eigenstate. This is the first measurement of the effective lifetime in this decay mode.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-017.htm

Study of WW boson production in association with beauty and charm

The associated production of a $W$ boson with a jet originating from either a light parton or heavy-flavor quark is studied in the forward region using proton-proton collisions. The analysis uses data corresponding to integrated luminosities of 1.0 and $2.0\,{\rm fb}^{-1}$ collected with the LHCb detector at center-of-mass energies of 7 and 8 TeV, respectively. The $W$ bosons are reconstructed using the $W\to\mu\nu$ decay and muons with a transverse momentum, $p_{\rm T}$, larger than 20 GeV in the pseudorapidity range $2.0 20$ GeV and $2.2 < \eta < 4.2$. The sum of the muon and jet momenta must satisfy $p_{\rm T} > 20$ GeV. The fraction of $W+$jet events that originate from beauty and charm quarks is measured, along with the charge asymmetries of the $W\!+\!b$ and $W\!+\!c$ production cross-sections. The ratio of the $W+$jet to $Z+$jet production cross-sections is also measured using the $Z\to\mu\mu$ decay. All results are in agreement with Standard Model predictions

Measurement of the mass and lifetime of the Ωb−\Omega_b^- baryon

A proton-proton collision data sample, corresponding to an integrated luminosity of 3 fb$^{-1}$ collected by LHCb at $\sqrt{s}=7$ and 8 TeV, is used to reconstruct $63\pm9$ $\Omega_b^-\to\Omega_c^0\pi^-$, $\Omega_c^0\to pK^-K^-\pi^+$ decays. Using the $\Xi_b^-\to\Xi_c^0\pi^-$, $\Xi_c^0\to pK^-K^-\pi^+$ decay mode for calibration, the lifetime ratio and absolute lifetime of the $\Omega_b^-$ baryon are measured to be \begin{align*} \frac{\tau_{\Omega_b^-}}{\tau_{\Xi_b^-}} &= 1.11\pm0.16\pm0.03, \\ \tau_{\Omega_b^-} &= 1.78\pm0.26\pm0.05\pm0.06~{\rm ps}, \end{align*} where the uncertainties are statistical, systematic and from the calibration mode (for $\tau_{\Omega_b^-}$ only). A measurement is also made of the mass difference, $m_{\Omega_b^-}-m_{\Xi_b^-}$, and the corresponding $\Omega_b^-$ mass, which yields \begin{align*} m_{\Omega_b^-}-m_{\Xi_b^-} &= 247.4\pm3.2\pm0.5~{\rm MeV}/c^2, \\ m_{\Omega_b^-} &= 6045.1\pm3.2\pm 0.5\pm0.6~{\rm MeV}/c^2. \end{align*} These results are consistent with previous measurements.Comment: 11 pages, 5 figures, All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-008.htm

Search for hidden-sector bosons in B0 ⁣→K∗0μ+μ−B^0 \!\to K^{*0}\mu^+\mu^- decays

A search is presented for hidden-sector bosons, $\chi$, produced in the decay ${B^0\!\to K^*(892)^0\chi}$, with $K^*(892)^0\!\to K^{+}\pi^{-}$ and $\chi\!\to\mu^+\mu^-$. The search is performed using $pp$-collision data corresponding to 3.0 fb$^{-1}$ collected with the LHCb detector. No significant signal is observed in the accessible mass range $214 \leq m({\chi}) \leq 4350$ MeV, and upper limits are placed on the branching fraction product $\mathcal{B}(B^0\!\to K^*(892)^0\chi)\times\mathcal{B}(\chi\!\to\mu^+\mu^-)$ as a function of the mass and lifetime of the $\chi$ boson. These limits are of the order of $10^{-9}$ for $\chi$ lifetimes less than 100 ps over most of the $m(\chi)$ range, and place the most stringent constraints to date on many theories that predict the existence of additional low-mass bosons.Comment: All figures and tables, along with supplementary material, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-036.htm