Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease
Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of pro...
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| Published in | The Journal of clinical investigation Vol. 118; no. 8; pp. 2796 - 2807 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
01.08.2008
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD. |
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| AbstractList | Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD. Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD.Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD. |
| Audience | Academic |
| Author | Nixon, Ralph A. Trinchese, Fabrizio Liu, Shumin Fa’, Mauro Zhang, Hong Yoshii, Narihiko Schmidt, Stephen D. Hidalgo, Ariel Yamaguchi, Hisako Mathews, Paul M. Arancio, Ottavio |
| AuthorAffiliation | 1 Department of Pathology and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, New York, USA. 2 Department of Psychiatry, New York University School of Medicine, New York, New York, USA. 3 Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA. 4 Pharmaceutical Research Division, Research Laboratory 1 (CNS), Mitsubishi Pharma Corporation, Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan. 5 Department of Cell Biology, New York University School of Medicine, New York, New York, USA |
| AuthorAffiliation_xml | – name: 1 Department of Pathology and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, New York, USA. 2 Department of Psychiatry, New York University School of Medicine, New York, New York, USA. 3 Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA. 4 Pharmaceutical Research Division, Research Laboratory 1 (CNS), Mitsubishi Pharma Corporation, Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan. 5 Department of Cell Biology, New York University School of Medicine, New York, New York, USA |
| Author_xml | – sequence: 1 givenname: Fabrizio surname: Trinchese fullname: Trinchese, Fabrizio – sequence: 2 givenname: Mauro surname: Fa’ fullname: Fa’, Mauro – sequence: 3 givenname: Shumin surname: Liu fullname: Liu, Shumin – sequence: 4 givenname: Hong surname: Zhang fullname: Zhang, Hong – sequence: 5 givenname: Ariel surname: Hidalgo fullname: Hidalgo, Ariel – sequence: 6 givenname: Stephen D. surname: Schmidt fullname: Schmidt, Stephen D. – sequence: 7 givenname: Hisako surname: Yamaguchi fullname: Yamaguchi, Hisako – sequence: 8 givenname: Narihiko surname: Yoshii fullname: Yoshii, Narihiko – sequence: 9 givenname: Paul M. surname: Mathews fullname: Mathews, Paul M. – sequence: 10 givenname: Ralph A. surname: Nixon fullname: Nixon, Ralph A. – sequence: 11 givenname: Ottavio surname: Arancio fullname: Arancio, Ottavio |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/18596919$$D View this record in MEDLINE/PubMed |
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| Snippet | Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation... |
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| SubjectTerms | Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Alzheimer Disease - physiopathology Alzheimer's disease Animals Biomedical research Calpain Calpain - antagonists & inhibitors Cell culture Cells, Cultured Control Cyclin-dependent kinases Disease Models, Animal Enzymes Glycoproteins - pharmacology Hippocampus - cytology Hippocampus - metabolism Homozygote Immunohistochemistry Kinases Leucine - analogs & derivatives Leucine - pharmacology Localization Memory Memory - drug effects Mice Mice, Transgenic Models, Neurological Neural transmission Peptides Phosphorylation Physiological aspects Proteins Synaptic Transmission - drug effects |
| Title | Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease |
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