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Satoko Matsumura,
Keiko Shinoda,
Mayumi Yamada,
Satoshi Yokojima,
Masafumi Inoue,
Takayuki Ohnishi,
Tetsuya Shimada,
Kazuya Kikuchi,
Dai Masui,
Shigeki Hashimoto, [......],
Yoshihiro Nakamura,
Kiyokazu Nemoto,
Yutaka Hasegawa,
Hisayoshi Takamoto,
Haruo Inoue,
Shinichiro Nakamura,
Yo-ichi Nabeshima,
David B. Teplow,
Masataka Kinjo,
Minako Hoshi
[show abstract]
[hide abstract]
ABSTRACT: Nonfibrillar assemblies of amyloid β-protein (Aβ) are considered to play primary roles in Alzheimer disease (AD). Elucidating
the assembly pathways of these specific aggregates is essential for understanding disease pathogenesis and developing knowledge-based
therapies. However, these assemblies cannot be monitored in vivo, and there has been no reliable in vitro monitoring method at low protein concentration. We have developed a highly sensitive in vitro monitoring method using fluorescence correlation spectroscopy (FCS) combined with transmission electron microscopy (TEM)
and toxicity assays. Using Aβ labeled at the N terminus or Lys16, we uncovered two distinct assembly pathways. One leads to highly toxic 10–15-nm spherical Aβ assemblies, termed amylospheroids
(ASPDs). The other leads to fibrils. The first step in ASPD formation is trimerization. ASPDs of ∼330 kDa in mass form from
these trimers after 5 h of slow rotation. Up to at least 24 h, ASPDs remain the dominant structures in assembly reactions.
Neurotoxicity studies reveal that the most toxic ASPDs are ∼128 kDa (∼32-mers). In contrast, fibrillogenesis begins with dimer
formation and then proceeds to formation of 15–40-nm spherical intermediates, from which fibrils originate after 15 h. Unlike
ASPD formation, the Lys16-labeled peptide disturbed fibril formation because the Aβ16–20 region is critical for this final step. These differences in the assembly pathways clearly indicated that ASPDs are not fibril
precursors. The method we have developed should facilitate identifying Aβ assembly steps at which inhibition may be beneficial.
Journal of Biological Chemistry 03/2011; 286(13):11555-11562. · 4.77 Impact Factor
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Satoko Matsumura,
Keiko Shinoda,
Mayumi Yamada,
Satoshi Yokojima,
Masafumi Inoue,
Takayuki Ohnishi,
Tetsuya Shimada,
Kazuya Kikuchi,
Dai Masui,
Shigeki Hashimoto, [......],
Yoshihiro Nakamura,
Kiyokazu Nemoto,
Yutaka Hasegawa,
Hisayoshi Takamoto,
Haruo Inoue,
Shinichiro Nakamura,
Yo-ichi Nabeshima,
David B Teplow,
Masataka Kinjo,
Minako Hoshi
[show abstract]
[hide abstract]
ABSTRACT: Nonfibrillar assemblies of amyloid β-protein (Aβ) are considered to play primary roles in Alzheimer disease (AD). Elucidating the assembly pathways of these specific aggregates is essential for understanding disease pathogenesis and developing knowledge-based therapies. However, these assemblies cannot be monitored in vivo, and there has been no reliable in vitro monitoring method at low protein concentration. We have developed a highly sensitive in vitro monitoring method using fluorescence correlation spectroscopy (FCS) combined with transmission electron microscopy (TEM) and toxicity assays. Using Aβ labeled at the N terminus or Lys(16), we uncovered two distinct assembly pathways. One leads to highly toxic 10-15-nm spherical Aβ assemblies, termed amylospheroids (ASPDs). The other leads to fibrils. The first step in ASPD formation is trimerization. ASPDs of ∼330 kDa in mass form from these trimers after 5 h of slow rotation. Up to at least 24 h, ASPDs remain the dominant structures in assembly reactions. Neurotoxicity studies reveal that the most toxic ASPDs are ∼128 kDa (∼32-mers). In contrast, fibrillogenesis begins with dimer formation and then proceeds to formation of 15-40-nm spherical intermediates, from which fibrils originate after 15 h. Unlike ASPD formation, the Lys(16)-labeled peptide disturbed fibril formation because the Aβ(16-20) region is critical for this final step. These differences in the assembly pathways clearly indicated that ASPDs are not fibril precursors. The method we have developed should facilitate identifying Aβ assembly steps at which inhibition may be beneficial.
Journal of Biological Chemistry 02/2011; 286(13):11555-62. · 4.77 Impact Factor
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Masanori Ono,
Kyoko Tanaka,
Nana Ikezawa,
Yusuke Kobayashi,
Yoko Inoue,
Megumi Yokota, Satoko Matsumura,
Ichiro Uehara,
Yoshihisa Hattori,
Takashi Kurahashi,
Tetsuya Shimada,
Hiroyuki Nakagawa
[show abstract]
[hide abstract]
ABSTRACT: We would like to report the case of a patient with fibroma of the omentum that resembled an ovarian tumor in the pelvis. Since primary tumours of the omentum are rare, there is a paucity of information about the biology of such tumors in the basic texts and literature. An ultrasound examination of the patient revealed a mass, likely of ovarian origin, which consisted of liquid and solid components. It was suspected to be a malignant ovarian tumor. However, laparotomy demonstrated it was an omental tumor. This case shows that it can be difficult to pre-operatively diagnose omental fibromas because of their close resemblance to ovarian tumors.
The Keio Journal of Medicine 12/2009; 58(4):234-6.
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Akihiko Noguchi, Satoko Matsumura,
Mari Dezawa,
Mari Tada,
Masako Yanazawa,
Akane Ito,
Manami Akioka,
Satoru Kikuchi,
Michio Sato,
Shouji Ideno, [......],
Atsushi Fukunari,
Shin-ichi Muramatsu,
Yutaka Itokazu,
Kazuki Sato,
Hitoshi Takahashi,
David B. Teplow,
Yo-ichi Nabeshima,
Akiyoshi Kakita,
Kazutomo Imahori,
Minako Hoshi
[show abstract]
[hide abstract]
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.
Journal of Biological Chemistry 11/2009; 284(47):32895-32905. · 4.77 Impact Factor
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Akihiko Noguchi, Satoko Matsumura,
Mari Dezawa,
Mari Tada,
Masako Yanazawa,
Akane Ito,
Manami Akioka,
Satoru Kikuchi,
Michio Sato,
Shouji Ideno, [......],
Atsushi Fukunari,
Shin-ichi Muramatsu,
Yutaka Itokazu,
Kazuki Sato,
Hitoshi Takahashi,
David B Teplow,
Yo-ichi Nabeshima,
Akiyoshi Kakita,
Kazutomo Imahori,
Minako Hoshi
[show abstract]
[hide abstract]
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.
Journal of Biological Chemistry 09/2009; 284(47):32895-905. · 4.77 Impact Factor
