title: Region- and age-dependent reductions of hippocampal long-term potentiation and NMDA to AMPA ratio in a genetic model of Alzheimer's disease.
abstract: To characterize the mechanisms underlying region- and age-dependent hippocampal synaptic dysfunction in Alzheimer's disease, we used transgenic CRND8 mice, expressing the Swedish-Indiana APP mutation. In 2-month-old mice, no β-amyloid plaques deposition, but the presence of soluble oligomers, were found in CA1 area but not in dentate gyrus (DG). At this age, long-term potentiation (LTP) was reduced selectively in CA1. In 6-month-old mice, the presence of soluble oligomers was accompanied by accumulation of β-amyloid plaques and decreased LTP in CA1 and DG regions. In both regions, the loss of LTP was linked to reduced N-methyl-D-aspartate (NMDA) to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) current ratio. The acetylcholine-esterase inhibitor, neostigmine rescued LTP in CA1 area at early stage of the disease but not after plaques deposition. Conversely, the NMDA receptor antagonist memantine restored LTP selectively in DG at later stages of the disease. Both these effects were associated with a normalization of the NMDA to AMPA ratio. The association between the recovery of LTP and the normalization of the NMDA to AMPA ratio provides information on new possible therapeutic strategies in Alzheimer's disease.
authors.affiliation: Clinica Neurologica, Università di Perugia, Department of Medicine, Ospedale S. Maria della Misericordia, Perugia, Italy; Laboratory of Neurophysiology, IRCCS, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sclip
authors.affiliation: Clinica Neurologica, Università di Perugia, Department of Medicine, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.affiliation: Clinica Neurologica, Università di Perugia, Department of Medicine, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: de Iure
authors.affiliation: Laboratory of Neurophysiology, IRCCS, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.affiliation: Clinica Neurologica, Università di Perugia, Department of Medicine, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Costa
authors.affiliation: Clinica Neurologica, Università di Perugia, Department of Medicine, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Borsello
authors.affiliation: Clinica Neurologica, Università di Perugia, Department of Medicine, Ospedale S. Maria della Misericordia, Perugia, Italy; Laboratory of Neurophysiology, IRCCS, Fondazione Santa Lucia, Rome, Italy. Electronic address: paolo.calabresi@unipg.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000375:Aging / Q000235:genetics* / Q000502:physiology*; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics*; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009154:Mutation; D016202:N-Methylaspartate / Q000378:metabolism*; D009388:Neostigmine / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D009388:Neostigmine; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
keywords: Beta-amyloid; CA1; Dentate gyrus; Long-term potentiation