2. Academic Validation
  3. Astrocytic AT1R deficiency ameliorates Aβ-induced cognitive deficits and synaptotoxicity through β-arrestin2 signaling

Astrocytic AT1R deficiency ameliorates Aβ-induced cognitive deficits and synaptotoxicity through β-arrestin2 signaling

  • Prog Neurobiol. 2023 Jun 22;102489. doi: 10.1016/j.pneurobio.2023.102489.
Xinyue Chen 1,  Ruiqi Gao 1,  Yizhi Song 1,  Tao Xu 1,  Liangyun Jin 2,  Wanning Zhang 1,  Ziyan Chen 1,  Hongqi Wang 1,  Wenxing Wu 1,  Suli Zhang 3,  Guitao Zhang 1,  Ning Zhang 4,  Lirong Chang 1,  Huirong Liu 3,  Hui Li 5,  Yan Wu 6
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Neural Regeneration and Repair, Department of Anatomy, School of Basic Medical Sciences, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, 100069, China.
  • 2 Electron Microscope Room of Central Laboratory, Capital Medical University, Beijing, 100069, China.
  • 3 Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
  • 4 Department of Neuropsychiatry and Behavioral Neurology and Clinical Psychology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • 5 Beijing Key Laboratory of Neural Regeneration and Repair, Department of Anatomy, School of Basic Medical Sciences, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, 100069, China. Electronic address: lihui5945@ccmu.edu.cn.
  • 6 Beijing Key Laboratory of Neural Regeneration and Repair, Department of Anatomy, School of Basic Medical Sciences, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, 100069, China. Electronic address: yanwu@ccmu.edu.cn.
PMID: 37355221 DOI: 10.1016/j.pneurobio.2023.102489
Abstract

Alzheimer's disease (AD) seriously influences human health, and there is no effective treatment to prevent or cure AD. Recent studies have shown that angiotensin II type 1 receptor (AT1R) blockers significantly reduce the prevalence of AD, while the precise role and mechanism of AT1R in AD remain obscure. In this study, for the first time, we identified that astrocytic but not neuronal AT1R levels were significantly increased in AD model rats and found that astrocyte-specific knockout of AT1R significantly ameliorated amyloid β (Aβ)-induced cognitive deficits and synaptotoxicity. Pretreating astrocytes with an AT1R blocker also alleviated Aβ-induced synaptotoxicity in the coculture system of hippocampal neurons and astrocytes. Moreover, AT1R could directly bind to Aβ1-42 and biasedly activate the astrocytic β-arrestin2 pathway, and biased inhibition of the astrocytic AT1R/β-arrestin2 pathway relieved Aβ-induced neurotoxicity. Furthermore, we demonstrated that astrocytic AT1R/β-arrestin2 pathway-mediated synaptotoxicity was associated with the aggregation of autophagosomes, which triggered the disordered degradation of Aβ. Our findings reveal a novel molecular mechanism of astrocytic AT1R in Aβ-induced neurodegeneration and might contribute to establishing new targets for AD prevention and therapy.

Keywords

Alzheimer's disease; Amyloid β; Angiotensin II type 1 receptor; Astrocyte; Autophagy.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z