Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment
Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity u...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/102509 https://orcid.org/0000-0001-9947-9071 https://orcid.org/0000-0003-1262-0592 |
| _version_ | 1826214940582608896 |
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| author | Seo, Jinsoo Zhou, Ying Rudenko, Andrii Cho, Sukhee Ota, Kristie Park, Christine Patzke, Holger Madabhushi, Ram Pan, Ling Guan, Ji-Song Delalle, Ivana Tsai, Li-Huei Giusti-Rodriguez, Paola Mungenast, Alison |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Seo, Jinsoo Zhou, Ying Rudenko, Andrii Cho, Sukhee Ota, Kristie Park, Christine Patzke, Holger Madabhushi, Ram Pan, Ling Guan, Ji-Song Delalle, Ivana Tsai, Li-Huei Giusti-Rodriguez, Paola Mungenast, Alison |
| author_sort | Seo, Jinsoo |
| collection | MIT |
| description | Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer’s disease (AD) resulted in an amelioration of β-amyloid (Aβ)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aβ-associated neurotoxicity and AD-like pathology. |
| first_indexed | 2024-09-23T16:12:47Z |
| format | Article |
| id | mit-1721.1/102509 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:12:47Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1025092022-09-29T18:59:34Z Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment Seo, Jinsoo Zhou, Ying Rudenko, Andrii Cho, Sukhee Ota, Kristie Park, Christine Patzke, Holger Madabhushi, Ram Pan, Ling Guan, Ji-Song Delalle, Ivana Tsai, Li-Huei Giusti-Rodriguez, Paola Mungenast, Alison Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Seo, Jinsoo Giusti-Rodriguez, Paola Zhou, Ying Rudenko, Andrii Cho, Sukhee Ota, Kristie T. Park, Christine Patzke, Holger Madabhushi, Ram Pan, Ling Mungenast, Alison Guan, Ji-Song Tsai, Li-Huei Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer’s disease (AD) resulted in an amelioration of β-amyloid (Aβ)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aβ-associated neurotoxicity and AD-like pathology. National Institutes of Health (U.S.) (Grant R01 NS051874) National Institutes of Health (U.S.) (Grant F31GM80055-03) Howard Hughes Medical Institute 2016-05-16T13:40:35Z 2016-05-16T13:40:35Z 2014-04 2013-11 Article http://purl.org/eprint/type/JournalArticle 00928674 1097-4172 http://hdl.handle.net/1721.1/102509 Seo, Jinsoo, Paola Giusti-Rodríguez, Ying Zhou, Andrii Rudenko, Sukhee Cho, Kristie T. Ota, Christine Park, et al. “Activity-Dependent P25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment.” Cell 157, no. 2 (April 2014): 486–498. https://orcid.org/0000-0001-9947-9071 https://orcid.org/0000-0003-1262-0592 en_US http://dx.doi.org/10.1016/j.cell.2014.01.065 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Seo, Jinsoo Zhou, Ying Rudenko, Andrii Cho, Sukhee Ota, Kristie Park, Christine Patzke, Holger Madabhushi, Ram Pan, Ling Guan, Ji-Song Delalle, Ivana Tsai, Li-Huei Giusti-Rodriguez, Paola Mungenast, Alison Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment |
| title | Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment |
| title_full | Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment |
| title_fullStr | Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment |
| title_full_unstemmed | Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment |
| title_short | Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment |
| title_sort | activity dependent p25 generation regulates synaptic plasticity and aβ induced cognitive impairment |
| url | http://hdl.handle.net/1721.1/102509 https://orcid.org/0000-0001-9947-9071 https://orcid.org/0000-0003-1262-0592 |
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