Reversal of neuronal tau pathology via adiponectin receptor activation
Abstract Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescue...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07391-z |
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| author | Eric R. McGregor Danny J. Lasky Olivia J. Rippentrop Josef P. Clark Samantha Wright Mathew V. Jones Rozalyn M. Anderson |
| author_facet | Eric R. McGregor Danny J. Lasky Olivia J. Rippentrop Josef P. Clark Samantha Wright Mathew V. Jones Rozalyn M. Anderson |
| author_sort | Eric R. McGregor |
| collection | DOAJ |
| description | Abstract Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b. The transcriptional response to AR included broad metabolic and functional pathways. Induction of lysosomal pathways involved activation of LC3 and p62, and restoration of neuronal outgrowth required the stress-responsive kinase JNK. Negative consequences of NFTs on mitochondrial activity, ATP production, and lipid stores were corrected. Defects in electrophysiological measures (e.g., resting potential, resistance, spiking profiles) were also corrected. These findings reveal a network linking mitochondrial function, cellular maintenance processes, and electrical aspects of neuronal function that can be targeted via adiponectin receptor activation. |
| format | Article |
| id | doaj-art-6bec160dd47245bc8d6f9e2f71d9f481 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-6bec160dd47245bc8d6f9e2f71d9f4812025-01-05T12:43:08ZengNature PortfolioCommunications Biology2399-36422025-01-018111410.1038/s42003-024-07391-zReversal of neuronal tau pathology via adiponectin receptor activationEric R. McGregor0Danny J. Lasky1Olivia J. Rippentrop2Josef P. Clark3Samantha Wright4Mathew V. Jones5Rozalyn M. Anderson6Division of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-MadisonDepartment of Neuroscience, University of Wisconsin–MadisonDepartment of Neuroscience, University of Wisconsin–MadisonDivision of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-MadisonDepartment of Neuroscience, University of Wisconsin–MadisonDepartment of Neuroscience, University of Wisconsin–MadisonDivision of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-MadisonAbstract Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b. The transcriptional response to AR included broad metabolic and functional pathways. Induction of lysosomal pathways involved activation of LC3 and p62, and restoration of neuronal outgrowth required the stress-responsive kinase JNK. Negative consequences of NFTs on mitochondrial activity, ATP production, and lipid stores were corrected. Defects in electrophysiological measures (e.g., resting potential, resistance, spiking profiles) were also corrected. These findings reveal a network linking mitochondrial function, cellular maintenance processes, and electrical aspects of neuronal function that can be targeted via adiponectin receptor activation.https://doi.org/10.1038/s42003-024-07391-z |
| spellingShingle | Eric R. McGregor Danny J. Lasky Olivia J. Rippentrop Josef P. Clark Samantha Wright Mathew V. Jones Rozalyn M. Anderson Reversal of neuronal tau pathology via adiponectin receptor activation Communications Biology |
| title | Reversal of neuronal tau pathology via adiponectin receptor activation |
| title_full | Reversal of neuronal tau pathology via adiponectin receptor activation |
| title_fullStr | Reversal of neuronal tau pathology via adiponectin receptor activation |
| title_full_unstemmed | Reversal of neuronal tau pathology via adiponectin receptor activation |
| title_short | Reversal of neuronal tau pathology via adiponectin receptor activation |
| title_sort | reversal of neuronal tau pathology via adiponectin receptor activation |
| url | https://doi.org/10.1038/s42003-024-07391-z |
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