Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity
Summary: Tau-mediated toxicity is associated with cognitive decline and Alzheimer’s disease (AD) progression. In particular, tau post-translational modifications (PTMs) are thought to generate aberrant tau species resulting in neuronal dysfunction. Despite being well characterized in postmortem AD b...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223009823 |
| _version_ | 1797812050527780864 |
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| author | Carli K. Opland Miles R. Bryan Braxton Harris Jake McGillion-Moore Xu Tian Youjun Chen Michelle S. Itano Graham H. Diering Rick B. Meeker Todd J. Cohen |
| author_facet | Carli K. Opland Miles R. Bryan Braxton Harris Jake McGillion-Moore Xu Tian Youjun Chen Michelle S. Itano Graham H. Diering Rick B. Meeker Todd J. Cohen |
| author_sort | Carli K. Opland |
| collection | DOAJ |
| description | Summary: Tau-mediated toxicity is associated with cognitive decline and Alzheimer’s disease (AD) progression. In particular, tau post-translational modifications (PTMs) are thought to generate aberrant tau species resulting in neuronal dysfunction. Despite being well characterized in postmortem AD brain, it is unclear how caspase-mediated C-terminal tau cleavage promotes neurodegeneration, as few studies have developed the models to dissect this pathogenic mechanism. Here, we show that proteasome impairment results in cleaved tau accumulation at the post-synaptic density (PSD), a process that is modulated by neuronal activity. Cleaved tau (at residue D421) impairs neuronal firing and causes inefficient initiation of network bursts, consistent with reduced excitatory drive. We propose that reduced neuronal activity, or silencing, is coupled to proteasome dysfunction, which drives cleaved tau accumulation at the PSD and subsequent synaptotoxicity. Our study connects three common themes in the progression of AD: impaired proteostasis, caspase-mediated tau cleavage, and synapse degeneration. |
| first_indexed | 2024-03-13T07:32:49Z |
| format | Article |
| id | doaj.art-b7f1210596e04e69bf9b211b6c093c4c |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-13T07:32:49Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-b7f1210596e04e69bf9b211b6c093c4c2023-06-04T04:24:20ZengElsevieriScience2589-00422023-06-01266106905Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicityCarli K. Opland0Miles R. Bryan1Braxton Harris2Jake McGillion-Moore3Xu Tian4Youjun Chen5Michelle S. Itano6Graham H. Diering7Rick B. Meeker8Todd J. Cohen9UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USAUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Neurology, University of North Carolina, Chapel Hill, NC 27599, USAUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USAUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USAUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USAUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USAUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Neurology, University of North Carolina, Chapel Hill, NC 27599, USAUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, USA; Corresponding authorSummary: Tau-mediated toxicity is associated with cognitive decline and Alzheimer’s disease (AD) progression. In particular, tau post-translational modifications (PTMs) are thought to generate aberrant tau species resulting in neuronal dysfunction. Despite being well characterized in postmortem AD brain, it is unclear how caspase-mediated C-terminal tau cleavage promotes neurodegeneration, as few studies have developed the models to dissect this pathogenic mechanism. Here, we show that proteasome impairment results in cleaved tau accumulation at the post-synaptic density (PSD), a process that is modulated by neuronal activity. Cleaved tau (at residue D421) impairs neuronal firing and causes inefficient initiation of network bursts, consistent with reduced excitatory drive. We propose that reduced neuronal activity, or silencing, is coupled to proteasome dysfunction, which drives cleaved tau accumulation at the PSD and subsequent synaptotoxicity. Our study connects three common themes in the progression of AD: impaired proteostasis, caspase-mediated tau cleavage, and synapse degeneration.http://www.sciencedirect.com/science/article/pii/S2589004223009823Molecular neuroscienceCellular neuroscience |
| spellingShingle | Carli K. Opland Miles R. Bryan Braxton Harris Jake McGillion-Moore Xu Tian Youjun Chen Michelle S. Itano Graham H. Diering Rick B. Meeker Todd J. Cohen Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity iScience Molecular neuroscience Cellular neuroscience |
| title | Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity |
| title_full | Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity |
| title_fullStr | Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity |
| title_full_unstemmed | Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity |
| title_short | Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity |
| title_sort | activity dependent tau cleavage by caspase 3 promotes neuronal dysfunction and synaptotoxicity |
| topic | Molecular neuroscience Cellular neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223009823 |
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