title: Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration.
abstract: Accumulation of β-amyloid (Aβ) in the brain is a key event in Alzheimer disease pathogenesis. Apolipoprotein (Apo) E is a lipid carrier protein secreted by astrocytes, which shows inherent affinity for Aβ and has been implicated in the receptor-mediated Aβ uptake by neurons. To characterize ApoE involvement in the intraneuronal Aβ accumulation and to investigate whether blocking the ApoE/Aβ interaction could reduce intraneuronal Aβ buildup, we used a noncontact neuronal-astrocytic co-culture system, where synthetic Aβ peptides were added into the media without or with cotreatment with Aβ12-28P, which is a nontoxic peptide antagonist of ApoE/Aβ binding. Compared with neurons cultured alone, intraneuronal Aβ content was significantly increased in neurons co-cultured with wild-type but not with ApoE knockout (KO) astrocytes. Neurons co-cultured with astrocytes also showed impaired intraneuronal degradation of Aβ, increased level of intraneuronal Aβ oligomers, and marked down-regulation of several synaptic proteins. Aβ12-28P treatment significantly reduced intraneuronal Aβ accumulation, including Aβ oligomer level, and inhibited loss of synaptic proteins. Furthermore, we showed significantly reduced intraneuronal Aβ accumulation in APPSW/PS1dE9/ApoE KO mice compared with APPSW/PS1dE9/ApoE targeted replacement mice that expressed various human ApoE isoforms. Data from our co-culture and in vivo experiments indicate an essential role of ApoE in the mechanism of intraneuronal Aβ accumulation and provide evidence that ApoE/Aβ binding antagonists can effectively prevent this process.
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Kuszczyk
authors.forename: Sandrine
authors.initials: S
authors.lastname: Sanchez
authors.forename: Joanna
authors.initials: J
authors.lastname: Pankiewicz
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Duszczyk
authors.forename: Maitea
authors.initials: M
authors.lastname: Guridi
authors.forename: Ayodeji A
authors.initials: AA
authors.lastname: Asuni
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sullivan
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sadowski
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001253:Astrocytes / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004705:Endocytosis; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D020033:Protein Isoforms