title: Memantine rescues transient cognitive impairment caused by high-molecular-weight aβ oligomers but not the persistent impairment induced by low-molecular-weight oligomers.
abstract: Brain accumulation of soluble amyloid-β oligomers (AβOs) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-weight (LMW) and high-molecular-weight (HMW) Aβ oligomers differentially impact synapses and memory. A single intracerebroventricular injection of LMW AβOs (10 pmol) induced rapid and persistent cognitive impairment in mice. On the other hand, memory deficit induced by HMW AβOs (10 pmol) was found to be reversible. While memory impairment in LMW oligomer-injected mice was associated with decreased hippocampal synaptophysin and GluN2B immunoreactivities, synaptic pathology was not detected in the hippocampi of HMW oligomer-injected mice. On the other hand, HMW oligomers, but not LMW oligomers, induced oxidative stress in hippocampal neurons. Memantine rescued both neuronal oxidative stress and the transient memory impairment caused by HMW oligomers, but did not prevent the persistent cognitive deficit induced by LMW oligomers. Results establish that different Aβ oligomer assemblies act in an orchestrated manner, inducing different pathologies and leading to synapse dysfunction. Furthermore, results suggest a mechanistic explanation for the limited efficacy of memantine in preventing memory loss in AD.
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil.
authors.forename: Cláudia P
authors.initials: CP
authors.lastname: Figueiredo
authors.forename: Julia R
authors.initials: JR
authors.lastname: Clarke
authors.forename: José Henrique
authors.initials: JH
authors.lastname: Ledo
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Ribeiro
authors.forename: Carine V
authors.initials: CV
authors.lastname: Costa
authors.forename: Helen M
authors.initials: HM
authors.lastname: Melo
authors.forename: Axa P
authors.initials: AP
authors.lastname: Mota-Sales
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Saraiva
authors.forename: William L
authors.initials: WL
authors.lastname: Klein
authors.forename: Adriano
authors.initials: A
authors.lastname: Sebollela
authors.forename: Fernanda G
authors.initials: FG
authors.lastname: De Felice
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008970:Molecular Weight; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D008559:Memantine