Research article
Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse
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* Corresponding author: Etsuro Matsubara etsuro@cc.hirosaki-u.ac.jp
1 Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan
2 Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Aomori, Japan
3 Immunas Pharma Incorporation, Kanagawa, Japan
4 Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Aichi, Japan
5 Department of Neurology, Okayama University School of Medicine, Okayama, Japan
6 Department of Life and Coordination-Complex Molecular Science, Institute for Molecular Science, Aichi, Japan
Molecular Neurodegeneration 2011, 6:20 doi:10.1186/1750-1326-6-20
Published: 6 March 2011Abstract
Background
Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid β (Aβ) oligomers. However, the pathological relevance of Aβ oligomers (AβOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AβOs remain to be determined.
Results
To specifically target toxic AβOs in vivo, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AβOs 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 AβOs 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 AβOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AβOs initiate the AD toxic process and intraneuronal AβOs may worsen neuronal degeneration and memory loss.
Conclusion
Now, we have evidence that HMW-AβOs 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.