Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-B accumulation modifier

Takashi Morihara, Noriyuki Hayashi, Mikiko Yokokoji, Hiroyasu Akatsu, Michael A. Silverman, Nobuyuki Kimura, Masahiro Sato, Yuhki Saito, Toshiharu Suzuki, Kanta Yanagida, Takashi S. Kodama, Toshihisa Tanaka, Masayasu Okochi, Shinji Tagami, Hiroaki Kazui, Takashi Kudo, Ryota Hashimoto, Naohiro Itoh, Kouhei Nishitomi, Yumi Yamaguchi-KabataTatsuhiko Tsunoda, Hironori Takamura, Taiichi Katayama, Ryo Kimura, Kouzin Kamino, Yoshio Hashizume, Masatoshi Takeda

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26 Citations (Scopus)


Alzheimer's disease (AD) is characterized by the accumulation of amyloid-B (AB). The genes that govern this process, however, have remained elusive. To this end, we combined distinct mouse strains with transcriptomics to directly identify disease-relevant genes. We show that AD model mice (APP-Tg) with DBA/2 genetic backgrounds have significantly lower levels of AB accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress AB accumulation. To avoid detecting secondarily affected genes by AB, we used non-Tg mice in the absence of AB pathology and selected candidate genes differently expressed in DBA/2 mice. Additional transcriptome analysis of APP-Tg mice with mixed genetic backgrounds revealed kinesin light chain-1 (Klc1) as an AB modifier, indicating a role for intracellular trafficking in AB accumulation. AB levels correlated with the expression levels of Klc1 splice variant E and the genotype of Klc1 in these APP-Tg mice. In humans, the expression levels of KLC1 variant E in brain and lymphocyte were significantly higher in AD patients compared with unaffected individuals. Finally, functional analysis using neuroblastoma cells showed that overexpression or knockdown of KLC1 variant E increases or decreases the production of AB, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of AB pathology. This unique combination of distinct mouse strains and model mice with transcriptomics is expected to be useful for the study of genetic mechanisms of other complex diseases.

Original languageEnglish
Pages (from-to)2638-2643
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
Publication statusPublished - 2014 Feb 18


  • Alternative splicing
  • Mouse-to-human translation


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