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P1‐306: Translational study: Refinement of DNA‐based Alzheimer's disease (AD) epitope vaccine in rabbits
Author(s) -
Davtyan Hayk,
Ghochikyan Anahit,
Petrushina Irina,
Hovakimyan Armine,
Movsesyan Nina,
Kiyatkin Anatoly,
Hannaman Drew,
Evans Claire F.,
Cribbs David,
Agadjanyan Michael
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.587
Subject(s) - epitope , immunogenicity , dna vaccination , virology , biology , immune system , epitope mapping , antibody , immunology , immunization
hippocampus, a brain area which is sensitive to Alzheimer’s Disease pathology, evaluating the effect of various concentrations of Ab1-40 on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs), 6 4b2 and 6 7. Particularly, we considered neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA. We also evaluated the effect of Ab1-40 on glycine release.Methods:We performed in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (hippocampal synaptosomes in superfusion), as previously described [Mura et al., 2010, 19(3):1041-53; Zappettini et al., 2011, 6(2):e16911]. Results: Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate, GABA and glycine. This effect was greatly inhibited by the highest concentrations of Ab1-40 considered (10mM in vivo and 100nM in vitro). With SDS-PAGE, all Ab1-40 preparations administered resolved to immunoreactive species consistent with Ab monomer.All the described effects were specific for Ab1-40 and for nicotinic secretory stimuli, as compared to depolarizing stimuli such as veratridine and K +. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (6 7 and 6 4b2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, GABA and glycine. High Ab1-40 concentrations (100nM) inhibited the overflow of all four neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Ab concentrations (1nM and 100pM) selectively acted on 6 7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not that ofGABAand glycine.Conclusions:The results reinforce the concept that Ab has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used. These effects may disrupt synaptic terminal regulation before leading to neurodegeneration.