Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice
Abstract Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal CA1 neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (...
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| Format: | Article |
| Language: | English |
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BMC
2019-12-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-019-0856-6 |
| _version_ | 1818388264328888320 |
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| author | Libin Zhou Joseph Flores Anastasia Noël Olivier Beauchet P. Jesper Sjöström Andrea C. LeBlanc |
| author_facet | Libin Zhou Joseph Flores Anastasia Noël Olivier Beauchet P. Jesper Sjöström Andrea C. LeBlanc |
| author_sort | Libin Zhou |
| collection | DOAJ |
| description | Abstract Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal CA1 neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (MB), a phenothiazine that inhibits caspases, alters Caspase-6-induced neurodegeneration and cognitive impairment in mice. Aged cognitively impaired Casp6-overexpressing mice were treated with methylene blue in drinking water for 1 month. Methylene blue treatment did not alter Caspase-6 levels, assessed by RT-PCR, western blot and immunohistochemistry, but inhibited fluorescently-labelled Caspase-6 activity in acute brain slice intact neurons. Methylene blue treatment rescued Caspase-6-induced episodic and spatial memory deficits measured by novel object recognition and Barnes maze, respectively. Methylene blue improved synaptic function of hippocampal CA1 neurons since theta-burst long-term potentiation (LTP), measured by field excitatory postsynaptic potentials (fEPSPs) in acute brain slices, was successfully induced in the Schaffer collateral-CA1 pathway in methylene blue-treated, but not in vehicle-treated, Caspase-6 mice. Increased neuroinflammation, measured by ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia numbers and subtypes, and glial fibrillary acidic protein (GFAP)-positive astrocytes, were decreased by methylene blue treatment. Therefore, methylene blue reverses Caspase-6-induced cognitive deficits by inhibiting Caspase-6, and Caspase-6-mediated neurodegeneration and neuroinflammation. Our results indicate that Caspase-6-mediated damage is reversible months after the onset of cognitive deficits and suggest that methylene blue could benefit Alzheimer disease patients by reversing Caspase-6-mediated cognitive decline. |
| first_indexed | 2024-12-14T04:23:04Z |
| format | Article |
| id | doaj.art-485d6f972eff467a8be1a38aa3a0acaa |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-14T04:23:04Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-485d6f972eff467a8be1a38aa3a0acaa2022-12-21T23:17:17ZengBMCActa Neuropathologica Communications2051-59602019-12-017111810.1186/s40478-019-0856-6Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged miceLibin Zhou0Joseph Flores1Anastasia Noël2Olivier Beauchet3P. Jesper Sjöström4Andrea C. LeBlanc5Lady Davis Institute for Medical Research at Jewish General HospitalLady Davis Institute for Medical Research at Jewish General HospitalLady Davis Institute for Medical Research at Jewish General HospitalLady Davis Institute for Medical Research at Jewish General HospitalCentre for Research in Neuroscience, the BRaIN Program, Department of Neurology and Neurosurgery, McGill University, The Research Institute of the McGill University Health Centre, Montreal General HospitalLady Davis Institute for Medical Research at Jewish General HospitalAbstract Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal CA1 neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (MB), a phenothiazine that inhibits caspases, alters Caspase-6-induced neurodegeneration and cognitive impairment in mice. Aged cognitively impaired Casp6-overexpressing mice were treated with methylene blue in drinking water for 1 month. Methylene blue treatment did not alter Caspase-6 levels, assessed by RT-PCR, western blot and immunohistochemistry, but inhibited fluorescently-labelled Caspase-6 activity in acute brain slice intact neurons. Methylene blue treatment rescued Caspase-6-induced episodic and spatial memory deficits measured by novel object recognition and Barnes maze, respectively. Methylene blue improved synaptic function of hippocampal CA1 neurons since theta-burst long-term potentiation (LTP), measured by field excitatory postsynaptic potentials (fEPSPs) in acute brain slices, was successfully induced in the Schaffer collateral-CA1 pathway in methylene blue-treated, but not in vehicle-treated, Caspase-6 mice. Increased neuroinflammation, measured by ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia numbers and subtypes, and glial fibrillary acidic protein (GFAP)-positive astrocytes, were decreased by methylene blue treatment. Therefore, methylene blue reverses Caspase-6-induced cognitive deficits by inhibiting Caspase-6, and Caspase-6-mediated neurodegeneration and neuroinflammation. Our results indicate that Caspase-6-mediated damage is reversible months after the onset of cognitive deficits and suggest that methylene blue could benefit Alzheimer disease patients by reversing Caspase-6-mediated cognitive decline.https://doi.org/10.1186/s40478-019-0856-6Alzheimer diseaseAxonal degenerationCaspase-6Caspase-6 inhibitorHippocampal CA1Hippocampal fibres |
| spellingShingle | Libin Zhou Joseph Flores Anastasia Noël Olivier Beauchet P. Jesper Sjöström Andrea C. LeBlanc Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice Acta Neuropathologica Communications Alzheimer disease Axonal degeneration Caspase-6 Caspase-6 inhibitor Hippocampal CA1 Hippocampal fibres |
| title | Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice |
| title_full | Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice |
| title_fullStr | Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice |
| title_full_unstemmed | Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice |
| title_short | Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice |
| title_sort | methylene blue inhibits caspase 6 activity and reverses caspase 6 induced cognitive impairment and neuroinflammation in aged mice |
| topic | Alzheimer disease Axonal degeneration Caspase-6 Caspase-6 inhibitor Hippocampal CA1 Hippocampal fibres |
| url | https://doi.org/10.1186/s40478-019-0856-6 |
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