Abstract
INTRODUCTION
More robust non-human primate models of Alzheimer’s disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD.
METHODS
We designed a CRISPR/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3′ and 5′ intron sequences of PSEN1 exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non-human primate model.
RESULTS
We observed early changes of AD-related pathological proteins (cerebrospinal fluid Aβ42 and phosphorylated tau) in PSEN1 mutant (ie, PSEN1-ΔE9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile PSEN1-ΔE9 cynomolgus monkeys.
DISCUSSION
PSEN1 mutant cynomolgus monkeys recapitulate AD-related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD-associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions.
Highlights
A dual-guide CRISPR/Cas9 system successfully mimics AD PSEN1-ΔE9 mutation by genomic excision of exon 9.
PSEN1 mutant cynomolgus monkey-derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased Aβ secretion.
Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile PSEN1 mutant cynomolgus monkeys.
Cerebrospinal fluid from juvenile PSEN1 mutant monkeys recapitulates early changes of AD-related pathological proteins (increased Aβ42 and phosphorylated tau).
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This post is Copyright: Mengqi Li,
Mingfeng Guan,
Jianbang Lin,
Kaichuan Zhu,
Jiayi Zhu,
Ming Guo,
Yinhu Li,
Yefei Chen,
Yijing Chen,
Ying Zou,
Daiqiang Wu,
Junxin Xu,
Wanying Yi,
Yingying Fan,
Shuangshuang Ma,
Yuewen Chen,
Jun Xu,
Lixin Yang,
Ji Dai,
Tao Ye,
Zhonghua Lu,
Yu Chen | July 8, 2024