Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice
Synapse loss is the strongest correlate of cognitive decline in Alzheimer's disease, and synapses are an attractive therapeutic target due to their plastic nature that allows for potential recovery with intervention. We have previously demonstrated in transgenic mice that form senile plaques th...
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| Format: | Article |
| Language: | English |
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Elsevier
2011-03-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999611000389X |
| _version_ | 1818573239615488000 |
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| author | Anete Rozkalne Bradley T. Hyman Tara L. Spires-Jones |
| author_facet | Anete Rozkalne Bradley T. Hyman Tara L. Spires-Jones |
| author_sort | Anete Rozkalne |
| collection | DOAJ |
| description | Synapse loss is the strongest correlate of cognitive decline in Alzheimer's disease, and synapses are an attractive therapeutic target due to their plastic nature that allows for potential recovery with intervention. We have previously demonstrated in transgenic mice that form senile plaques that dendrites surrounding plaques become dystrophic and lose postsynaptic dendritic spines. Furthermore, we found strong evidence that plaque-associated dendritic changes are mediated by calcineurin, a calcium-dependent phosphatase involved in cell signaling, using in vitro models and genetically encoded inhibitors in mouse models. In this study, we pharmacologically inhibited calcineurin with FK506 treatment to test the hypothesis that calcineurin inhibition will allow recovery of plaque-associated synapse loss. We found that in plaque bearing transgenic mice, short term (1 week) FK506 treatment results in an amelioration of dendritic spine loss. We also observe an effect on spine morphology in wild-type mice with FK506 treatment. These data show that systemic FK506 administration, and hence calcineurin inhibition, may be neuroprotective for amyloid beta induced synaptic alterations. |
| first_indexed | 2024-12-15T00:08:32Z |
| format | Article |
| id | doaj.art-af0dd59c04fc4d6b9a189384e08661b1 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-15T00:08:32Z |
| publishDate | 2011-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-af0dd59c04fc4d6b9a189384e08661b12022-12-21T22:42:40ZengElsevierNeurobiology of Disease1095-953X2011-03-01413650654Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model miceAnete Rozkalne0Bradley T. Hyman1Tara L. Spires-Jones2MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USACorresponding author. 114 16th Street, Charlestown, MA 02129, USA. Fax: +1 617 724 1480.; MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USAMassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USASynapse loss is the strongest correlate of cognitive decline in Alzheimer's disease, and synapses are an attractive therapeutic target due to their plastic nature that allows for potential recovery with intervention. We have previously demonstrated in transgenic mice that form senile plaques that dendrites surrounding plaques become dystrophic and lose postsynaptic dendritic spines. Furthermore, we found strong evidence that plaque-associated dendritic changes are mediated by calcineurin, a calcium-dependent phosphatase involved in cell signaling, using in vitro models and genetically encoded inhibitors in mouse models. In this study, we pharmacologically inhibited calcineurin with FK506 treatment to test the hypothesis that calcineurin inhibition will allow recovery of plaque-associated synapse loss. We found that in plaque bearing transgenic mice, short term (1 week) FK506 treatment results in an amelioration of dendritic spine loss. We also observe an effect on spine morphology in wild-type mice with FK506 treatment. These data show that systemic FK506 administration, and hence calcineurin inhibition, may be neuroprotective for amyloid beta induced synaptic alterations.http://www.sciencedirect.com/science/article/pii/S096999611000389XAlzheimerDendritic spineFK506TacrolimusSynapseTransgenic |
| spellingShingle | Anete Rozkalne Bradley T. Hyman Tara L. Spires-Jones Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice Neurobiology of Disease Alzheimer Dendritic spine FK506 Tacrolimus Synapse Transgenic |
| title | Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice |
| title_full | Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice |
| title_fullStr | Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice |
| title_full_unstemmed | Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice |
| title_short | Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice |
| title_sort | calcineurin inhibition with fk506 ameliorates dendritic spine density deficits in plaque bearing alzheimer model mice |
| topic | Alzheimer Dendritic spine FK506 Tacrolimus Synapse Transgenic |
| url | http://www.sciencedirect.com/science/article/pii/S096999611000389X |
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