TY - JOUR
T1 - Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse
AU - Takamura, Ayumi
AU - Okamoto, Yasuhide
AU - Kawarabayashi, Takeshi
AU - Yokoseki, Tatsuki
AU - Shibata, Masao
AU - Mouri, Akihiko
AU - Nabeshima, Toshitaka
AU - Sun, Hui
AU - Abe, Koji
AU - Urisu, Tsuneo
AU - Yamamoto, Naoki
AU - Shoji, Mikio
AU - Yanagisawa, Katsuhiko
AU - Michikawa, Makoto
AU - Matsubara, Etsuro
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid for Advanced Brain Scientific Project-from the Ministry of Education, Culture, Sports, Science and Technology, Japan [15016080 and 16015284 to E.M.]; and the Research Grant for Longevity Sciences from the Ministry of Health, Labour and Welfare [17A-1 to E.M.].
PY - 2011
Y1 - 2011
N2 - Background: Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid (A) oligomers. However, the pathological relevance of A oligomers (AOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AOs remain to be determined. Results: To specifically target toxic AOs in vivo, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AOs larger than 35-mers and pentamers on Blue native polyacrylamide gel electrophoresis, respectively. Biophysical and structural analysis by atomic force microscopy (AFM) revealed that neurotoxic 1A9 and 2C3 oligomeric conformers displayed non-fibrilar, relatively spherical structure. Of note, such AOs were taken up by neuroblastoma (SH-SY5Y) cell, resulted in neuronal death. In humans, immunohistochemical analysis employing 1A9 or 2C3 revealed that 1A9 and 2C3 stain intraneuronal granules accumulated in the perikaryon of pyramidal neurons and some diffuse plaques. Fluoro Jade-B binding assay also revealed 1A9- or 2C3-stained neurons, indicating their impending degeneration. In a long-term low-dose prophylactic trial using active 1A9 or 2C3 antibody, we found that passive immunization protected a mouse model of Alzheimer's disease (AD) from memory deficits, synaptic degeneration, promotion of intraneuronal AOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AOs initiate the AD toxic process and intraneuronal AOs may worsen neuronal degeneration and memory loss. Conclusion: Now, we have evidence that HMW-AOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.
AB - Background: Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid (A) oligomers. However, the pathological relevance of A oligomers (AOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AOs remain to be determined. Results: To specifically target toxic AOs in vivo, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AOs larger than 35-mers and pentamers on Blue native polyacrylamide gel electrophoresis, respectively. Biophysical and structural analysis by atomic force microscopy (AFM) revealed that neurotoxic 1A9 and 2C3 oligomeric conformers displayed non-fibrilar, relatively spherical structure. Of note, such AOs were taken up by neuroblastoma (SH-SY5Y) cell, resulted in neuronal death. In humans, immunohistochemical analysis employing 1A9 or 2C3 revealed that 1A9 and 2C3 stain intraneuronal granules accumulated in the perikaryon of pyramidal neurons and some diffuse plaques. Fluoro Jade-B binding assay also revealed 1A9- or 2C3-stained neurons, indicating their impending degeneration. In a long-term low-dose prophylactic trial using active 1A9 or 2C3 antibody, we found that passive immunization protected a mouse model of Alzheimer's disease (AD) from memory deficits, synaptic degeneration, promotion of intraneuronal AOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AOs initiate the AD toxic process and intraneuronal AOs may worsen neuronal degeneration and memory loss. Conclusion: Now, we have evidence that HMW-AOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.
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U2 - 10.1186/1750-1326-6-20
DO - 10.1186/1750-1326-6-20
M3 - Article
C2 - 21375782
AN - SCOPUS:79952196722
SN - 1750-1326
VL - 6
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 20
ER -