title: Early accumulation of intracellular fibrillar oligomers and late congophilic amyloid angiopathy in mice expressing the Osaka intra-Aβ APP mutation.
abstract: Pathogenic amyloid-β peptide precursor (APP) mutations clustered around position 693 of APP-position 22 of the Aβ sequence--are commonly associated with congophilic amyloid angiopathy (CAA) and intracerebral hemorrhages. In contrast, the Osaka (E693Δ) intra-Aβ APP mutation shows a recessive pattern of inheritance that leads to AD-like dementia despite low brain amyloid on in vivo positron emission tomography imaging. Here, we investigated the effects of the Osaka APP mutation on Aβ accumulation and deposition in vivo using a newly generated APP transgenic mouse model (E22ΔAβ) expressing the Osaka mutation together with the Swedish (K670N/M671L) double mutation. E22ΔAβ mice exhibited reduced α-processing of APP and early accumulation of intraneuronal fibrillar Aβ oligomers associated with cognitive deficits. In line with our in vitro findings that recombinant E22Δ-mutated Aβ peptides form amyloid fibrils, aged E22ΔAβ mice showed extracellular CAA deposits in leptomeningeal cerebellar and cortical vessels. In vitro results from thioflavin T aggregation assays with recombinant Aβ peptides revealed a yet unknown antiamyloidogenic property of the E693Δ mutation in the heterozygous state and an inhibitory effect of E22Δ Aβ42 on E22Δ Aβ40 fibrillogenesis. Moreover, E22Δ Aβ42 showed a unique aggregation kinetics lacking exponential fibril growth and poor seeding effects on wild-type Aβ aggregation. These results provide a possible explanation for the recessive trait of inheritance of the Osaka APP mutation and the apparent lack of amyloid deposition in E693Δ mutation carriers.
authors.affiliation: Division of Psychiatry Research, University of Zurich, Zurich, Switzerland. luka.kulic@bli.uzh.ch
authors.forename: L
authors.initials: L
authors.lastname: Kulic
authors.forename: J
authors.initials: J
authors.lastname: McAfoose
authors.forename: T
authors.initials: T
authors.lastname: Welt
authors.forename: C
authors.initials: C
authors.lastname: Tackenberg
authors.forename: C
authors.initials: C
authors.lastname: Späni
authors.forename: F
authors.initials: F
authors.lastname: Wirth
authors.forename: V
authors.initials: V
authors.lastname: Finder
authors.forename: U
authors.initials: U
authors.lastname: Konietzko
authors.forename: M
authors.initials: M
authors.lastname: Giese
authors.forename: A
authors.initials: A
authors.lastname: Eckert
authors.forename: K
authors.initials: K
authors.lastname: Noriaki
authors.forename: T
authors.initials: T
authors.lastname: Shimizu
authors.forename: K
authors.initials: K
authors.lastname: Murakami
authors.forename: K
authors.initials: K
authors.lastname: Irie
authors.forename: S
authors.initials: S
authors.lastname: Rasool
authors.forename: C
authors.initials: C
authors.lastname: Glabe
authors.forename: C
authors.initials: C
authors.lastname: Hock
authors.forename: R M
authors.initials: RM
authors.lastname: Nitsch
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor