Reduction of mNAT1/hNAT2 Contributes to Cerebral Endothelial Necroptosis and Aβ Accumulation in Alzheimer’s Disease
Chengyu Zou, Lauren Mifflin, Zhirui Hu, Tian Zhang, Bing Shan, Huibing Wang, Xin Xing, Hong Zhu, Xian Adiconis, Joshua Z. Levin, Fupeng Li, Chuan‐Fa Liu, Jun S. Liu, Junying Yuan
Abstract
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.