title: Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function.
abstract: A subtle but chronic alteration in metabolic balance between amyloid-beta peptide (Abeta) anabolic and catabolic activities is thought to cause Abeta accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of Abeta 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 Abeta 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 Abeta-degrading enzyme, in the brain elevates oligomeric forms of Abeta 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 Abeta oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms.
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.forename: Hideko
authors.initials: H
authors.lastname: Kokubo
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nakajima
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suemoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003071:Cognition / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D013569:Synapses / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D015260:Neprilysin