Molecular neuropathology

Apr 1985 - Dec 1985

Assistant in Neurosurgery, Nagoya University Hospital

Jan 1986 - Jul 1987

Chief in Neurosurgery, Shizuoka-Kousei Hospital

Jul 1987 - Jan 1989

Postgraduate scholarship, National Institute of Neurosurgery, Budapest, Hungary

Feb 1989

Trainee, Allgemeines Krankenhaus (AKH), Vienna, Austria

Mar 1989 - Jul 1989

Registrar, Department of Neurosugery, Nagoya Daini Red Cross Hospital

July 1989 - Oct 1997

Instructor in Neurosurgery, Nagoya University Hospital

Dec 1994 - Feb 1995

Teaching staff of Japan International Cooperation, Center (JICA) in Sanjay Gandhi Postgraduate, Institute of Medical Sciences at Lucknow, India

Nov 1997 - Dec 1997

Overseas research foundation by Japanese Ministry of Education, Department of neurosurgery, The hospital for sick children, Toronto University, Toronto, Ontario, Canada

Nov 1997 - Mar 2000

Assistant Professor in Neurosurgery, Nagoya University Hospital

April 2000 - May 2002

Associate Professor in Bio-Medicine, Nagoya University School of Medicine

June 2002 - May 2008

Associate Professor in The Center for Genetic and Regenerative Medicine, Nagoya University Hospital

June 2008 - present

Professor, Department of Neurosurgery, Nagoya University Graduate School of Medicine

Clarification of pathogenesis and development of therapeutics for Alzheimer disease

One of the fundamental questions regarding the pathogenesis of Alzheimer’s disease (AD) is how the monomeric, nontoxic amyloid ß-protein (Aß) is converted to its toxic assemblies in the brain. In the case of familial AD, the expression of responsible genes likely facilitates Aß assembly through enhancement of Aß production; however, no evidence has yet been provided suggesting that the degree of Aß production increases in sporadic AD, the major form of the disease.

We previously identified a novel Aß species in an AD brain, that is characterized by its binding to the GM1 ganglioside (GM1). On the basis of the molecular characteristics of this GM1-bound Aß (GAß), we hypothesized that Aß adopts an altered conformation through its binding to GM1, and then, GAß acts as a seed for amyloid fibril formation in an AD brain. To validate our hypothesis, we attempted to raise a novel monoclonal antibody specific to GAß using in vitro immunization technique and through genetic class-switch procedure. Having established the binding specificity of the antibody (4396C), we then performed immunohistochemical study to detect GAß in the AD brains in order to confirm that GAß is endogenously generated in the brain. Careful immunohistochemistry allowed us to obtain intraneuronal staining of 4396C in the sections. To further confirm the immunohistochemical detection of GAß, we examined fresh brains of nonhuman primates, which naturally develop Aß deposition after age. The cerebral cortices of seven animals at different ages were examined. In the sections obtained from the aged animals, a number of neurons were strongly immunostained by 4396C with a granular pattern. Furthermore, GAß was also immunoprecipitated by 4396C only in the samples from the cerebral cortices of the aged animal. These results indicate that GAß is generated in the brain.

In regard to the cell biological mechanism underlying GAß generation, we have paid particular attention to the previous findings of endocytic pathway abnormalities, including the enlargement of early endosomes and the up-regulation of Rab5, selectively observed in neurons of brains affected with sporadic AD and Down syndrome. We have recently tested whether the GAß-dependent amyloid fibril formation on the cell surface can be accelerated in association with the endocytic pathway abnormalities, which was induced by treatment with chloroquine, which is well known to perturb endocytic transport, or by suppression of Rab7, which plays a critical role in endocytic pathway. In these experiments, enhanced GAß-dependent amyloid fibril formation from exogenously added soluble Aß was clearly observed on the cell surface. These results suggest that endocytic dysfunction contributes to the amyloid fibril formation through facilitation of GAß generation.

A line of our studies so far suggest that the alteration in ganglioside expression on the surface of neurons is a crucial environmental factor for inducing the assembly and deposition of Aß in the brain. A challenge for future studies is to elucidate the mechanism underlying GAß generation in the brain, which may provide new insights into the pathophysiology of AD. Moreover, on the basis of the fact that the conformation of GAß is distinct from those of soluble Aßs and assembled Aßs as amyloid fibrils, GAß can be a target to develop a novel therapeutic strategy for AD.

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3. Yuyama K et al. Accelerated release of exosome-associated GM1 ganglioside (GM1) by endocytic pathway abnormality: another putative pathway for GM1-induced amyloid fibril formation. J. Neurochem. 105: 217-224 (2008)
4. Yamamoto N et al. Age-dependent high-density clustering of GM1 ganglioside at presynaptic neuritic terminals promotes amyloid ß-protein fibrillogenesis. Biochim. Biophys. Acta. 1778：2717-2726, (2008)
5. Yamamoto N et al. A ganglioside-induced toxix soluble Aß assembly: Its enhanced formation from Aß bearing the Arctic mutation. J. Biol. Chem. 282: 2646-2655 (2007)
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8. Yamamoto N et al. Assembly of hereditary amyloid ß-protein variants in the presence of favorable gangliosides. FEBS Lett. 579: 2185-2190 (2005)
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