Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity

Ma Huifang, Sylvain E Lesne, Linda Kotilinek, Jill V. Steidl-Nichols, Mathew A Sherman, Linda Younkin, Steven Younkin, Colleen L Forster, Nicolas Sergeant, André Delacourte, Robert Vassar, Martin Citron, Paulo Kofuji, Linda M. Boland, Karen H Ashe

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)8167-8172
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number19
DOIs
StatePublished - May 8 2007

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Neuronal Plasticity
Amyloid beta-Protein Precursor
Enzymes
Alzheimer Disease
Serum Amyloid A Protein
Calcium Signaling
Amyloid Plaques
Memory Disorders
Amyloid
Synaptic Transmission
Transgenic Mice
Genes
Hippocampus
Learning
Pathology
Neurons
Peptides

Keywords

  • Learning
  • Transgenic

Cite this

Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. / Huifang, Ma; Lesne, Sylvain E; Kotilinek, Linda; Steidl-Nichols, Jill V.; Sherman, Mathew A; Younkin, Linda; Younkin, Steven; Forster, Colleen L; Sergeant, Nicolas; Delacourte, André; Vassar, Robert; Citron, Martin; Kofuji, Paulo; Boland, Linda M.; Ashe, Karen H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 19, 08.05.2007, p. 8167-8172.

Research output: Contribution to journalArticle

Huifang, Ma ; Lesne, Sylvain E ; Kotilinek, Linda ; Steidl-Nichols, Jill V. ; Sherman, Mathew A ; Younkin, Linda ; Younkin, Steven ; Forster, Colleen L ; Sergeant, Nicolas ; Delacourte, André ; Vassar, Robert ; Citron, Martin ; Kofuji, Paulo ; Boland, Linda M. ; Ashe, Karen H. / Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 19. pp. 8167-8172.
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AU - Lesne, Sylvain E

AU - Kotilinek, Linda

AU - Steidl-Nichols, Jill V.

AU - Sherman, Mathew A

AU - Younkin, Linda

AU - Younkin, Steven

AU - Forster, Colleen L

AU - Sergeant, Nicolas

AU - Delacourte, André

AU - Vassar, Robert

AU - Citron, Martin

AU - Kofuji, Paulo

AU - Boland, Linda M.

AU - Ashe, Karen H

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N2 - 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.

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