Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity
| Autor: | Linda Kotilinek, Karen H. Ashe, Huifang Ma, Linda H. Younkin, Colleen L. Forster, Jill Steidl-Nichols, Martin Citron, Steven G. Younkin, Nicolas Sergeant, Mathew A. Sherman, André Delacourte, Robert Vassar, Sylvain Lesné, Paulo Kofuji, Linda M. Boland |
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| Rok vydání: | 2007 |
| Předmět: |
Transgene
Long-Term Potentiation Mice Transgenic Neurotransmission Biology Amyloid beta-Protein Precursor Mice Memory mental disorders medicine Amyloid precursor protein Animals Aspartic Acid Endopeptidases Calcium signaling Neuronal Plasticity Multidisciplinary Long-term potentiation Biological Sciences Cell biology Mice Inbred C57BL medicine.anatomical_structure Biochemistry Synapses Synaptic plasticity biology.protein Neuron Amyloid Precursor Protein Secretases Amyloid precursor protein secretase |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:8167-8172 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid-β protein (Aβ), which forms amyloid plaques in Alzheimer's disease (AD), secreted APPα (sAPPα) which enhances memory, and the APP intracellular domain (AICD), which has been implicated in the regulation of gene transcription and calcium signaling. The β-site APP cleaving enzyme 1 (BACE1) cleaves APP in an activity-dependent manner to form Aβ, AICD, and secreted APPβ. Because this neural activity was shown to diminish synaptic transmission in vitro [Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) Neuron 37:925–937], the prevailing notion has been that this pathway diminishes synaptic function. Here we investigated the role of this pathway in vivo . We studied transgenic mice overproducing APP that do not develop AD pathology or memory deficits but instead exhibit enhanced spatial memory. We showed enhanced synaptic plasticity in the hippocampus that depends on prior synaptic activity. We found that the enhanced memory and synaptic plasticity are abolished by the ablation of one or both copies of the BACE1 gene, leading to a significant decrease in AICD but not of any other APP cleavage products. In contrast to the previously described negative effect of BACE1-mediated cleavage of APP on synaptic function in vitro , our in vivo work indicates that BACE1-mediated cleavage of APP can facilitate learning, memory, and synaptic plasticity. |
| Databáze: | OpenAIRE |
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