Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in alzheimer's disease
The contribution and mechanism of cerebrovascular pathology in Alzheimer's disease (AD) pathogenesis are still unclear. Here, we show that venular and capillary cerebral endothelial cells (ECs) are selectively vulnerable to necroptosis in AD. We identify reduced cerebromicrovascular expression...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/146010 |
| _version_ | 1826121005581467648 |
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| author | Zou, Chengyu Mifflin, Lauren Hu, Zhirui Zhang, Tian Shan, Bing Wang, Huibing Xing, Xin Zhu, Hong Adiconis, Xian Levin, Joshua Z. Li, Fupeng Liu, Chuan-Fa Liu, Jun S. Yuan, Junying |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Zou, Chengyu Mifflin, Lauren Hu, Zhirui Zhang, Tian Shan, Bing Wang, Huibing Xing, Xin Zhu, Hong Adiconis, Xian Levin, Joshua Z. Li, Fupeng Liu, Chuan-Fa Liu, Jun S. Yuan, Junying |
| author_sort | Zou, Chengyu |
| collection | NTU |
| description | The contribution and mechanism of cerebrovascular pathology in Alzheimer's disease (AD) pathogenesis are still unclear. Here, we show that venular and capillary cerebral endothelial cells (ECs) are selectively vulnerable to necroptosis in AD. We identify reduced cerebromicrovascular expression of murine N-acetyltransferase 1 (mNat1) in two AD mouse models and hNat2, the human ortholog of mNat1 and a genetic risk factor for type-2 diabetes and insulin resistance, in human AD. mNat1 deficiency in Nat1-/- mice and two AD mouse models promotes blood-brain barrier (BBB) damage and endothelial necroptosis. Decreased mNat1 expression induces lysosomal degradation of A20, an important regulator of necroptosis, and LRP1β, a key component of LRP1 complex that exports Aβ in cerebral ECs. Selective restoration of cerebral EC expression of mNAT1 delivered by adeno-associated virus (AAV) rescues cerebromicrovascular levels of A20 and LRP1β, inhibits endothelial necroptosis and activation, ameliorates mitochondrial fragmentation, reduces Aβ deposits, and improves cognitive function in the AD mouse model. |
| first_indexed | 2024-10-01T05:25:41Z |
| format | Journal Article |
| id | ntu-10356/146010 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:25:41Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1460102023-02-28T16:58:34Z Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in alzheimer's disease Zou, Chengyu Mifflin, Lauren Hu, Zhirui Zhang, Tian Shan, Bing Wang, Huibing Xing, Xin Zhu, Hong Adiconis, Xian Levin, Joshua Z. Li, Fupeng Liu, Chuan-Fa Liu, Jun S. Yuan, Junying School of Biological Sciences Science::Biological sciences Necroptosis Alzheimer’s Disease The contribution and mechanism of cerebrovascular pathology in Alzheimer's disease (AD) pathogenesis are still unclear. Here, we show that venular and capillary cerebral endothelial cells (ECs) are selectively vulnerable to necroptosis in AD. We identify reduced cerebromicrovascular expression of murine N-acetyltransferase 1 (mNat1) in two AD mouse models and hNat2, the human ortholog of mNat1 and a genetic risk factor for type-2 diabetes and insulin resistance, in human AD. mNat1 deficiency in Nat1-/- mice and two AD mouse models promotes blood-brain barrier (BBB) damage and endothelial necroptosis. Decreased mNat1 expression induces lysosomal degradation of A20, an important regulator of necroptosis, and LRP1β, a key component of LRP1 complex that exports Aβ in cerebral ECs. Selective restoration of cerebral EC expression of mNAT1 delivered by adeno-associated virus (AAV) rescues cerebromicrovascular levels of A20 and LRP1β, inhibits endothelial necroptosis and activation, ameliorates mitochondrial fragmentation, reduces Aβ deposits, and improves cognitive function in the AD mouse model. Published version 2021-01-21T02:13:41Z 2021-01-21T02:13:41Z 2020 Journal Article Zou, C., Mifflin, L., Hu, Z., Zhang, T., Shan, B., Wang, H., . . . Yuan, J. (2020). Reduction of mNAT1/hNAT2 Contributes to Cerebral Endothelial Necroptosis and Aβ Accumulation in Alzheimer’s Disease. Cell Reports, 33(10), 108447-. doi:10.1016/j.celrep.2020.108447 2211-1247 https://hdl.handle.net/10356/146010 10.1016/j.celrep.2020.108447 33296651 2-s2.0-85097467044 10 33 en Cell reports © 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) application/pdf |
| spellingShingle | Science::Biological sciences Necroptosis Alzheimer’s Disease Zou, Chengyu Mifflin, Lauren Hu, Zhirui Zhang, Tian Shan, Bing Wang, Huibing Xing, Xin Zhu, Hong Adiconis, Xian Levin, Joshua Z. Li, Fupeng Liu, Chuan-Fa Liu, Jun S. Yuan, Junying Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in alzheimer's disease |
| title | Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in alzheimer's disease |
| title_full | Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in alzheimer's disease |
| title_fullStr | Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in alzheimer's disease |
| title_full_unstemmed | Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in alzheimer's disease |
| title_short | Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in alzheimer's disease |
| title_sort | reduction of mnat1 hnat2 contributes to cerebral endothelial necroptosis and aβ accumulation in alzheimer s disease |
| topic | Science::Biological sciences Necroptosis Alzheimer’s Disease |
| url | https://hdl.handle.net/10356/146010 |
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