title: N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits.
abstract: N-truncated Aβ4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Aβ peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aβ4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aβ4-42 is as toxic as pyroglutamate Aβ3-42 and Aβ1-42. In line with these findings, treatment of wildtype mice using intraventricular Aβ injection induced significant working memory deficits with Aβ4-42, pyroglutamate Aβ3-42 and Aβ1-42. Transgenic mice expressing Aβ4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aβ4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aβ4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction.
authors.affiliation: Division of Molecular Psychiatry, Georg-August-University Goettingen, University Medicine Goettingen, von-Siebold-Strasse 5, 37075, Goettingen, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Bouter
authors.forename: Katharina
authors.initials: K
authors.lastname: Dietrich
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Wittnam
authors.forename: Nasrollah
authors.initials: N
authors.lastname: Rezaei-Ghaleh
authors.forename: Thierry
authors.initials: T
authors.lastname: Pillot
authors.forename: Sophie
authors.initials: S
authors.lastname: Papot-Couturier
authors.forename: Thomas
authors.initials: T
authors.lastname: Lefebvre
authors.forename: Frederick
authors.initials: F
authors.lastname: Sprenger
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology*; D000682:Amyloid / Q000737:chemistry / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics* / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D005260:Female; D005333:Fetus / Q000166:cytology; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008970:Molecular Weight; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013028:Space Perception / Q000502:physiology
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides