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J. Biol. Chem., Vol. 281, Issue 26, 17941-17951, June 30, 2006

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Neprilysin-sensitive Synapse-associated Amyloid- Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function^*

Shu-Ming Huang¹, Akihiro Mouri¹, Hideko Kokubo^¶1, Ryuichi Nakajima, Takahiro Suemoto, Makoto Higuchi^||, Matthias Staufenbiel^**, Yukihiro Noda, Haruyasu Yamaguchi^¶, Toshitaka Nabeshima, Takaomi C. Saido², and Nobuhisa Iwata³

From the Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8560, Japan, ^¶Gunma University School of Health Sciences, Maebashi, Gunma 371-8514, Japan, ^||Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba 263-8555, Japan, ^**Nervous System Department, Novartis Institutes of Biomedical Research Basel, CH-4002 Basel, Switzerland, and Division of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, Aichi 468-8503, Japan

A subtle but chronic alteration in metabolic balance between amyloid- peptide (A) anabolic and catabolic activities is thought to cause A accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of A in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed A accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13–16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major A-degrading enzyme, in the brain elevates oligomeric forms of A at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce A oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms.

Received for publication, February 13, 2006 , and in revised form, April 11, 2006.

^* This study was supported by research grants from RIKEN Brain Science Institute, Grants-in-aid for Scientific Research on Priority Areas 12210019, 13035055, and 17025046 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Grant-in-aid for Scientific Research (C) 17500244 from the Japan Society for the Promotion of Science. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Tel.: 81-48-462-1111 (ext. 7614); Fax: 81-48-467-9716; E-mail: saido{at}brain.riken.jp. ³ To whom correspondence may be addressed: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Tel.: 81-48-462-1111 (ext. 7614); Fax: 81-48-467-9716; E-mail: iwatan{at}brain.riken.jp.

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