title: Inhibition of the polyamine system counteracts β-amyloid peptide-induced memory impairment in mice: involvement of extrasynaptic NMDA receptors.
abstract: In Alzheimer's disease (AD), the β-amyloid peptide (Aβ) has been causally linked to synaptic dysfunction and cognitive impairment. Several studies have shown that N-Methyl-D-Aspartate receptors (NMDAR) activation is involved in the detrimental actions of Aβ. Polyamines, like spermidine and spermine, are positive modulators of NMDAR function and it has been shown that their levels are regulated by Aβ. In this study we show here that interruption of NMDAR modulation by polyamines through blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aβ25-35-induced memory impairment in mice in a novel object recognition task. Incubation of hippocampal cell cultures with Aβ25-35 (10 µM) significantly increased the nuclear accumulation of Jacob, which is a hallmark of NMDAR activation. The Aβ-induced nuclear translocation of Jacob was blocked upon application of traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM), suggesting that activation of the polyamine binding site at NMDAR located probably at extrasynaptic sites might underlie the cognitive deficits of Aβ25-35-treated mice. Extrasynaptic NMDAR activation in primary neurons results in a stripping of synaptic contacts and simplification of neuronal cytoarchitecture. Aβ25-35 application in hippocampal primary cell cultures reduced dendritic spine density and induced alterations on spine morphology. Application of traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM) reversed these effects of Aβ25-35. Taken together these data provide evidence that polyamine modulation of extrasynaptic NMDAR signaling might be involved in Aβ pathology.
authors.affiliation: Biochemistry and Molecular Biology Department, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil; Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Guilherme Monteiro
authors.initials: GM
authors.lastname: Gomes
authors.affiliation: Biochemistry and Molecular Biology Department, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Gerusa Duarte
authors.initials: GD
authors.lastname: Dalmolin
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bär
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Karpova
authors.affiliation: Physiology and Pharmacology Department, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Carlos Fernando
authors.initials: CF
authors.lastname: Mello
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kreutz
authors.affiliation: Biochemistry and Molecular Biology Department, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Maribel Antonello
authors.initials: MA
authors.lastname: Rubin
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D001665:Binding Sites; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D010880:Piperidines / Q000494:pharmacology; D011073:Polyamines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013095:Spermidine / Q000008:administration & dosage / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D001645:Biguanides; C544462:Jacob protein, mouse; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010880:Piperidines; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; C074636:amyloid beta-protein (25-35); C006624:arcaine; C095106:traxoprodil mesylate; D013095:Spermidine