Neprilysin-sensitive synapse-associated amyloid-β peptide oligomers impair neuronal plasticity and cognitive function

Shu Ming Huang, Akihiro Mouri, Hideko Kokubo, Ryuichi Nakajima, Takahiro Suemoto, Makoto Higuchi, Matthias Staufenbiel, Yukihiro Noda, Haruyasu Yamaguchi, Toshitaka Nabeshima, Takaomi C. Saido, Nobuhisa Iwata

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141 Citations (Scopus)

Abstract

A subtle but chronic alteration in metabolic balance between amyloid-β peptide(Aβ)anabolic and catabolic activities is thought to cause Aβ accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of Aβ 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 Aβ 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 Aβ-degrading enzyme, in the brain elevates oligomeric forms of Aβ 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 Aβ oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms.

Original languageEnglish
Pages (from-to)17941-17951
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number26
DOIs
Publication statusPublished - 30-06-2006

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Huang, S. M., Mouri, A., Kokubo, H., Nakajima, R., Suemoto, T., Higuchi, M., Staufenbiel, M., Noda, Y., Yamaguchi, H., Nabeshima, T., Saido, T. C., & Iwata, N. (2006). Neprilysin-sensitive synapse-associated amyloid-β peptide oligomers impair neuronal plasticity and cognitive function. Journal of Biological Chemistry, 281(26), 17941-17951. https://doi.org/10.1074/jbc.M601372200