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J. Biol. Chem., Vol. 282, Issue 4, 2646-2655, January 26, 2007

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A Ganglioside-induced Toxic Soluble A Assembly

ITS ENHANCED FORMATION FROM ABEARING THE ARCTIC MUTATION^*

Naoki Yamamoto, Etsuro Matsubara, Sumihiro Maeda^¶, Hirohisa Minagawa, Akihiko Takashima^¶, Wakako Maruyama^||, Makoto Michikawa, and Katsuhiko Yanagisawa¹

From the Departments of Alzheimer's Disease Research and ^||Geriatric Medicine, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu 474-8522, Japan, the Japan Society for the Promotion of Sciences, Tokyo 102-8472, Japan, and the ^¶Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, Wako 351-0198, Japan

The mechanism underlying plaque-independent neuronal death in Alzheimer disease (AD), which is probably responsible for early cognitive decline in AD patients, remains unclarified. Here, we show that a toxic soluble A assembly (TA) is formed in the presence of liposomes containing GM1 ganglioside more rapidly and to a greater extent from a hereditary variant-type ("Arctic") A than from wild-type A.TA is also formed from soluble A through incubation with natural neuronal membranes prepared from aged mouse brains in a GM1 ganglioside-dependent manner. An oligomer-specific antibody (anti-Oligo) significantly suppresses TA toxicity. Biophysical and structural analyses by atomic force microscopy and size exclusion chromatography revealed that TA is spherical with diameters of 10–20 nm and molecular masses of 200–300 kDa. TA induces neuronal death, which is abrogated by the small interfering RNA-mediated knockdown of nerve growth factor receptors, including TrkA and p75 neurotrophin receptor. Our results suggest that soluble A assemblies, such as TA, can cause plaque-independent neuronal death that favorably occurs in nerve growth factor-dependent neurons in the cholinergic basal forebrain in AD.

Received for publication, June 29, 2006 , and in revised form, November 27, 2006.

^* This study was supported by Grant-in-aid for Scientific Research on Priority Areas 1700220004, Research on Pathomechanisms of Brain Disorders, from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu 474-8522, Japan. Tel.: 81-562-44-5651 (ext. 5002); Fax: 81-562-44-6594; E-mail: katuhiko{at}nils.go.jp.

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