Isolation and characterization of patient-derived, toxic, high mass Amyloid β-protein (Aβ) assembly from Alzheimer disease brains

Akihiko Noguchi, Satoko Matsumura, Mari Dezawa, Mari Tada, Masako Yanazawa, Akane Ito, Manami Akioka, Satoru Kikuchi, Michio Sato, Munehiro Noda, Atsusbi Fukunari, Shin Ichi Muramatsu, Yutaka Itokazu, Kazuki Sato, Hitoshi Takahashi, David B. Teplow, Yo Ichi Nabeshima, Akiyoshi Kakita, Kazutomo Imahori, Minako Hoshi

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Abstract

Amyloid β-protein (Aβ) 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, Aβ 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 Aβ 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, Aβ-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 Aβ assemblies.

Original languageEnglish (US)
Pages (from-to)32895-32905
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number47
DOIs
StatePublished - Nov 20 2009

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Patient Isolation
Serum Amyloid A Protein
Poisons
Brain
Alzheimer Disease
Antibodies
Toxicity
Lewy Bodies
Neurons
Synaptic Transmission
Neurodegenerative Diseases
Neurodegenerative diseases
4-aminospiroperidol
Ligands
Phenotype
Oligomers
Dimers
Monomers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Isolation and characterization of patient-derived, toxic, high mass Amyloid β-protein (Aβ) assembly from Alzheimer disease brains. / Noguchi, Akihiko; Matsumura, Satoko; Dezawa, Mari; Tada, Mari; Yanazawa, Masako; Ito, Akane; Akioka, Manami; Kikuchi, Satoru; Sato, Michio; Noda, Munehiro; Fukunari, Atsusbi; Muramatsu, Shin Ichi; Itokazu, Yutaka; Sato, Kazuki; Takahashi, Hitoshi; Teplow, David B.; Nabeshima, Yo Ichi; Kakita, Akiyoshi; Imahori, Kazutomo; Hoshi, Minako.

In: Journal of Biological Chemistry, Vol. 284, No. 47, 20.11.2009, p. 32895-32905.

Research output: Contribution to journalArticle

Noguchi, A, Matsumura, S, Dezawa, M, Tada, M, Yanazawa, M, Ito, A, Akioka, M, Kikuchi, S, Sato, M, Noda, M, Fukunari, A, Muramatsu, SI, Itokazu, Y, Sato, K, Takahashi, H, Teplow, DB, Nabeshima, YI, Kakita, A, Imahori, K & Hoshi, M 2009, 'Isolation and characterization of patient-derived, toxic, high mass Amyloid β-protein (Aβ) assembly from Alzheimer disease brains', Journal of Biological Chemistry, vol. 284, no. 47, pp. 32895-32905. https://doi.org/10.1074/jbc.M109.000208
Noguchi, Akihiko ; Matsumura, Satoko ; Dezawa, Mari ; Tada, Mari ; Yanazawa, Masako ; Ito, Akane ; Akioka, Manami ; Kikuchi, Satoru ; Sato, Michio ; Noda, Munehiro ; Fukunari, Atsusbi ; Muramatsu, Shin Ichi ; Itokazu, Yutaka ; Sato, Kazuki ; Takahashi, Hitoshi ; Teplow, David B. ; Nabeshima, Yo Ichi ; Kakita, Akiyoshi ; Imahori, Kazutomo ; Hoshi, Minako. / Isolation and characterization of patient-derived, toxic, high mass Amyloid β-protein (Aβ) assembly from Alzheimer disease brains. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 47. pp. 32895-32905.
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AU - Yanazawa, Masako

AU - Ito, Akane

AU - Akioka, Manami

AU - Kikuchi, Satoru

AU - Sato, Michio

AU - Noda, Munehiro

AU - Fukunari, Atsusbi

AU - Muramatsu, Shin Ichi

AU - Itokazu, Yutaka

AU - Sato, Kazuki

AU - Takahashi, Hitoshi

AU - Teplow, David B.

AU - Nabeshima, Yo Ichi

AU - Kakita, Akiyoshi

AU - Imahori, Kazutomo

AU - Hoshi, Minako

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