Open AccessCRISPR/Cas9-mediated CysLT1R deletion reverses synaptic failure, amyloidosis and cognitive impairment in APP/PS1 mice
Author(s) -
Fang Chen,
Shunchang Fang,
Yifeng Du,
Arijit Ghosh,
Miranda N. Reed,
Yan Long,
Vishnu Suppiramaniam,
Shuming Tang,
Hao Hong
Publication year - 2021
Publication title -
aging
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.473
H-Index - 90
ISSN - 1945-4589
DOI - 10.18632/aging.202501
Subject(s) - crispr , neuroinflammation , synaptic plasticity , neuroscience , gene knockdown , knockout mouse , biology , amyloid precursor protein , gene knockout , microbiology and biotechnology , alzheimer's disease , medicine , immunology , receptor , gene , genetics , disease , inflammation
As a major pathological hallmark of Alzheimer's disease (AD), amyloid-β (Aβ) is regarded as a causative factor for cognitive impairment. Extensive studies have found Aβ induces a series of pathophysiological responses, finally leading to memory loss in AD. Our previous results demonstrated that cysteinyl leukotrienes receptor 1 (CysLT 1 R) antagonists improved exogenous Aβ-induced memory impairment. But the role of CysLT 1 R in AD and its underlying mechanisms still remain elusive. In this study, we investigated CysLT 1 R levels in AD patients and APP/PS1 mice. We also generated APP/PS1-CysLT 1 R -/- mice by clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated CysLT 1 R deletion in APP/PS1 mice and studied the effect of CysLT 1 R knockout on amyloidogenesis, synapse structure and plasticity, cognition, neuroinflammation, and kynurenine pathway. These attributes were also studied after lentivirus-mediated knockdown of CysLT 1 R gene in APP/PS1 mice. We found that CysLT 1 R knockout or knockdown could conserve synaptic structure and plasticity, and improve cognition in APP/PS1 mice. These effects were associated with concurrent decreases in amyloid processing, reduced neuroinflammation and suppression of the kynurenine pathway. Our study demonstrates that CysLT 1 R deficiency can mediate several beneficial effects against AD pathogenesis, and genetic/pharmacological ablation of this protein could be a potential therapeutic option for AD.