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 language | English |
|---|---|
| Pages (from-to) | 17941-17951 |
| Number of pages | 11 |
| Journal | Journal of Biological Chemistry |
| Volume | 281 |
| Issue number | 26 |
| DOIs | |
| Publication status | Published - 30-06-2006 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
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Neprilysin-sensitive synapse-associated amyloid-β peptide oligomers impair neuronal plasticity and cognitive function. / Huang, Shu Ming; Mouri, Akihiro; Kokubo, Hideko; Nakajima, Ryuichi; Suemoto, Takahiro; Higuchi, Makoto; Staufenbiel, Matthias; Noda, Yukihiro; Yamaguchi, Haruyasu; Nabeshima, Toshitaka; Saido, Takaomi C.; Iwata, Nobuhisa.
In: Journal of Biological Chemistry, Vol. 281, No. 26, 30.06.2006, p. 17941-17951.Research output: Contribution to journal › Article
TY - JOUR
T1 - Neprilysin-sensitive synapse-associated amyloid-β peptide oligomers impair neuronal plasticity and cognitive function
AU - Huang, Shu Ming
AU - Mouri, Akihiro
AU - Kokubo, Hideko
AU - Nakajima, Ryuichi
AU - Suemoto, Takahiro
AU - Higuchi, Makoto
AU - Staufenbiel, Matthias
AU - Noda, Yukihiro
AU - Yamaguchi, Haruyasu
AU - Nabeshima, Toshitaka
AU - Saido, Takaomi C.
AU - Iwata, Nobuhisa
PY - 2006/6/30
Y1 - 2006/6/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33745808762&partnerID=8YFLogxK
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U2 - 10.1074/jbc.M601372200
DO - 10.1074/jbc.M601372200
M3 - Article
VL - 281
SP - 17941
EP - 17951
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 26
ER -