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Title: Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in alzheimer's disease
Authors: 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
Keywords: Science::Biological sciences
Issue Date: 2020
Source: 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
Journal: Cell reports
Abstract: 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.
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2020.108447
Schools: School of Biological Sciences 
Rights: © 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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