Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models
Amyloid-induced neurodegeneration plays a central role in Alzheimer's disease (AD) pathogenesis. Here, we show that telomerase reverse transcriptase (TERT) haploinsufficiency decreases BDNF and increases amyloid-β (Aβ) precursor in murine brain. Moreover, prior to disease onset, the TERT locus...
| Main Authors: | , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2023
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| Online Access: | https://hdl.handle.net/1721.1/150409 |
| _version_ | 1826205625277743104 |
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| author | Shim, Hong Seok Horner, James W Wu, Chang-Jiun Li, Jiexi Lan, Zheng D Jiang, Shan Xu, Xueping Hsu, Wen-Hao Zal, Tomasz Flores, Ivonne I Deng, Pingna Lin, Yuan-Ta Tsai, Li-Huei Wang, Y Alan DePinho, Ronald A |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Shim, Hong Seok Horner, James W Wu, Chang-Jiun Li, Jiexi Lan, Zheng D Jiang, Shan Xu, Xueping Hsu, Wen-Hao Zal, Tomasz Flores, Ivonne I Deng, Pingna Lin, Yuan-Ta Tsai, Li-Huei Wang, Y Alan DePinho, Ronald A |
| author_sort | Shim, Hong Seok |
| collection | MIT |
| description | Amyloid-induced neurodegeneration plays a central role in Alzheimer's disease (AD) pathogenesis. Here, we show that telomerase reverse transcriptase (TERT) haploinsufficiency decreases BDNF and increases amyloid-β (Aβ) precursor in murine brain. Moreover, prior to disease onset, the TERT locus sustains accumulation of repressive epigenetic marks in murine and human AD neurons, implicating TERT repression in amyloid-induced neurodegeneration. To test the impact of sustained TERT expression on AD pathobiology, AD mouse models were engineered to maintain physiological levels of TERT in adult neurons, resulting in reduced Aβ accumulation, improved spine morphology, and preserved cognitive function. Mechanistically, integrated profiling revealed that TERT interacts with β-catenin and RNA polymerase II at gene promoters and upregulates gene networks governing synaptic signaling and learning processes. These TERT-directed transcriptional activities do not require its catalytic activity nor telomerase RNA. These findings provide genetic proof-of-concept for somatic TERT gene activation therapy in attenuating AD progression including cognitive decline. |
| first_indexed | 2024-09-23T13:16:04Z |
| format | Article |
| id | mit-1721.1/150409 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:16:04Z |
| publishDate | 2023 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1504092023-04-05T03:25:38Z Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models Shim, Hong Seok Horner, James W Wu, Chang-Jiun Li, Jiexi Lan, Zheng D Jiang, Shan Xu, Xueping Hsu, Wen-Hao Zal, Tomasz Flores, Ivonne I Deng, Pingna Lin, Yuan-Ta Tsai, Li-Huei Wang, Y Alan DePinho, Ronald A Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Amyloid-induced neurodegeneration plays a central role in Alzheimer's disease (AD) pathogenesis. Here, we show that telomerase reverse transcriptase (TERT) haploinsufficiency decreases BDNF and increases amyloid-β (Aβ) precursor in murine brain. Moreover, prior to disease onset, the TERT locus sustains accumulation of repressive epigenetic marks in murine and human AD neurons, implicating TERT repression in amyloid-induced neurodegeneration. To test the impact of sustained TERT expression on AD pathobiology, AD mouse models were engineered to maintain physiological levels of TERT in adult neurons, resulting in reduced Aβ accumulation, improved spine morphology, and preserved cognitive function. Mechanistically, integrated profiling revealed that TERT interacts with β-catenin and RNA polymerase II at gene promoters and upregulates gene networks governing synaptic signaling and learning processes. These TERT-directed transcriptional activities do not require its catalytic activity nor telomerase RNA. These findings provide genetic proof-of-concept for somatic TERT gene activation therapy in attenuating AD progression including cognitive decline. 2023-04-04T17:49:03Z 2023-04-04T17:49:03Z 2021 2023-04-04T17:45:07Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/150409 Shim, Hong Seok, Horner, James W, Wu, Chang-Jiun, Li, Jiexi, Lan, Zheng D et al. 2021. "Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models." Nature Aging, 1 (12). en 10.1038/S43587-021-00146-Z Nature Aging Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Shim, Hong Seok Horner, James W Wu, Chang-Jiun Li, Jiexi Lan, Zheng D Jiang, Shan Xu, Xueping Hsu, Wen-Hao Zal, Tomasz Flores, Ivonne I Deng, Pingna Lin, Yuan-Ta Tsai, Li-Huei Wang, Y Alan DePinho, Ronald A Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models |
| title | Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models |
| title_full | Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models |
| title_fullStr | Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models |
| title_full_unstemmed | Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models |
| title_short | Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models |
| title_sort | telomerase reverse transcriptase preserves neuron survival and cognition in alzheimer s disease models |
| url | https://hdl.handle.net/1721.1/150409 |
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