title: Isolation and characterization of patient-derived, toxic, high mass amyloid beta-protein (Abeta) assembly from Alzheimer disease brains.
abstract: Amyloid beta-protein (Abeta) assemblies are thought to play primary roles in Alzheimer disease (AD). They are considered to acquire surface tertiary structures, not present in physiologic monomers, that are responsible for exerting toxicity, probably through abnormal interactions with their target(s). Therefore, Abeta assemblies having distinct surface tertiary structures should cause neurotoxicity through distinct mechanisms. Aiming to clarify the molecular basis of neuronal loss, which is a central phenotype in neurodegenerative diseases such as AD, we report here the selective immunoisolation of neurotoxic 10-15-nm spherical Abeta assemblies termed native amylospheroids (native ASPDs) from AD and dementia with Lewy bodies brains, using ASPD tertiary structure-dependent antibodies. In AD patients, the amount of native ASPDs was correlated with the pathologic severity of disease. Native ASPDs are anti-pan oligomer A11 antibody-negative, high mass (>100 kDa) assemblies that induce degeneration particularly of mature neurons, including those of human origin, in vitro. Importantly, their immunospecificity strongly suggests that native ASPDs have a distinct surface tertiary structure from other reported assemblies such as dimers, Abeta-derived diffusible ligands, and A11-positive assemblies. Only ASPD tertiary structure-dependent antibodies could block ASPD-induced neurodegeneration. ASPDs bind presynaptic target(s) on mature neurons and have a mode of toxicity different from those of other assemblies, which have been reported to exert their toxicity through binding postsynaptic targets and probably perturbing glutamatergic synaptic transmission. Thus, our findings indicate that native ASPDs with a distinct toxic surface induce neuronal loss through a different mechanism from other Abeta assemblies.
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences, Tokyo 194-8511, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Noguchi
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsumura
authors.forename: Mari
authors.initials: M
authors.lastname: Dezawa
authors.forename: Mari
authors.initials: M
authors.lastname: Tada
authors.forename: Masako
authors.initials: M
authors.lastname: Yanazawa
authors.forename: Akane
authors.initials: A
authors.lastname: Ito
authors.forename: Manami
authors.initials: M
authors.lastname: Akioka
authors.forename: Satoru
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Michio
authors.initials: M
authors.lastname: Sato
authors.forename: Shouji
authors.initials: S
authors.lastname: Ideno
authors.forename: Munehiro
authors.initials: M
authors.lastname: Noda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukunari
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Itokazu
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sato
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.forename: Yo-ichi
authors.initials: Y
authors.lastname: Nabeshima
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Kazutomo
authors.initials: K
authors.lastname: Imahori
authors.forename: Minako
authors.initials: M
authors.lastname: Hoshi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000302:isolation & purification; D001921:Brain / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; D018094:Receptors, Metabotropic Glutamate