LY379268 Does Not Have Long-Term Procognitive Effects nor Attenuate Glutamatergic Signaling in A beta PP/PS1 Mice

Hascup, Kevin N.; Britz, Jesse; Findley, Caleigh A.; Tischkau, Shelley; Hascup, Erin R. ✉

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: JOURNAL OF ALZHEIMER'S DISEASE 1387-2877 1875-8908 68 (3) pp. 1193-1209 2019
  • SJR Scopus - Medicine (miscellaneous): D1
    Chronically elevated basal glutamate levels are hypothesized to attenuate detection of physiological signals thereby inhibiting memory formation and retrieval, while inducing excitotoxicity-mediated neurodegeneration observed in Alzheimer's disease (AD). However, current medication targeting the glutamatergic system, such as memantine, shows limited efficacy and is unable to decelerate disease progression, possibly because it modulates postsynaptic N-methyl-D-aspartate receptors rather than glutamate release or clearance. To determine if decreasing presynaptic glutamate release leads to long-term procognitive effects, we treated A beta PP/PS1 mice with LY379268 (3.0 mg/kg; i.p.), a metabotropic glutamate receptor (mGluR)(2/3) agonist from 2-6 months of age when elevated glutamate levels are first observed but cognition is unaffected. C57BL/6J genetic background control mice and another cohort of A beta PP/PS1 mice received normal saline (i.p.) as vehicle controls. After 6 months off treatment, mice receiving LY379268 did not show long-term improvement as assessed by the Morris water maze (MWM) spatial learning and memory paradigm. Following MWM, mice were isoflurane anesthetized and a glutamate selective microelectrode was used to measure in vivo basal and stimulus-evoked glutamate release and clearance independently from the dentate, CA3, and CA1 hippocampal subregions. Immunohistochemistry was used to measure hippocampal astrogliosis and plaque pathology. Similar to previous studies, we observed elevated basal glutamate, stimulus evoked glutamate release, and astrogliosis in A beta PP/PS1 vehicle mice versus C57BL/6J mice. Treatment with LY379268 did not attenuate these responses nor diminish plaque pathology. The current study builds upon previous research demonstrating hyperglutamatergic hippocampal signaling in A beta PP/PS1 mice; however, long-term therapeutic efficacy of LY379268 in A beta PP/PS1 was not observed.
    Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
    2020-08-05 06:13