Multimodal analyses of a non-human primate model harboring mutant amyloid precursor protein transgenes driven by the human EF1α promoter.

Sho Yoshimatsu, Fumiko Seki, Junko Okahara, Hirotaka Watanabe, Hiroki Sasaguri, Yawara Haga, Jun ichi Hata, Tsukasa Sanosaka, Takashi Inoue, Takayuki Mineshige, Chia Ying Lee, Haruka Shinohara, Yoko Kurotaki, Yuji Komaki, Noriyuki Kishi, Ayaka Y. Murayama, Yuji Nagai, Takafumi Minamimoto, Masafumi Yamamoto, Mayutaka NakajimaZhi Zhou, Akisa Nemoto, Tsukika Sato, Takeshi Ikeuchi, Naruhiko Sahara, Satoru Morimoto, Seiji Shiozawa, Takaomi C. Saido, Erika Sasaki, Hideyuki Okano

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease (AD) is the leading cause of dementia which afflicts tens of millions of people worldwide. Despite many scientific progresses to dissect the AD's molecular basis from studies on various mouse models, it has been suffered from evolutionary species differences. Here, we report generation of a non-human primate (NHP), common marmoset model ubiquitously expressing Amyloid-beta precursor protein (APP) transgenes with the Swedish (KM670/671NL) and Indiana (V717F) mutations. The transgene integration of generated two transgenic marmosets (TG1&TG2) was thoroughly investigated by genomic PCR, whole-genome sequencing, and fluorescence in situ hybridization. By reprogramming, we confirmed the validity of transgene expression in induced neurons in vitro. Moreover, we discovered structural changes in specific brain regions of transgenic marmosets by magnetic resonance imaging analysis, including in the entorhinal cortex and hippocampus. In immunohistochemistry, we detected increased Aβ plaque-like structures in TG1 brain at 7 years old, although evident neuronal loss or glial inflammation was not observed. Thus, this study summarizes our attempt to establish an NHP AD model. Although the transgenesis approach alone seemed not sufficient to fully recapitulate AD in NHPs, it may be beneficial for drug development and further disease modeling by combination with other genetically engineered models and disease-inducing approaches.

Original languageEnglish
Pages (from-to)49-61
Number of pages13
JournalNeuroscience Research
Volume185
DOIs
Publication statusPublished - 2022 Dec

Keywords

  • Alzheimer's disease
  • Common marmoset
  • Magnetic resonance imaging
  • Non-human primate
  • Reprogramming
  • Transgenesis
  • Whole-genome sequencing

ASJC Scopus subject areas

  • Neuroscience(all)

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