Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-β accumulation modifier.
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ). 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 Aβ accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress Aβ accumulation. To avoid detecting secondarily affected genes by Aβ, we used non-Tg mice in the absence of Aβ 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 Aβ modifier, indicating a role for intracellular trafficking in Aβ accumulation. Aβ 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 Aβ, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of Aβ 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.
Department of Psychiatry, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Takashi
T
Morihara
Noriyuki
N
Hayashi
Mikiko
M
Yokokoji
Hiroyasu
H
Akatsu
Michael A
MA
Silverman
Nobuyuki
N
Kimura
Masahiro
M
Sato
Yuhki
Y
Saito
Toshiharu
T
Suzuki
Kanta
K
Yanagida
Takashi S
TS
Kodama
Toshihisa
T
Tanaka
Masayasu
M
Okochi
Shinji
S
Tagami
Hiroaki
H
Kazui
Takashi
T
Kudo
Ryota
R
Hashimoto
Naohiro
N
Itoh
Kouhei
K
Nishitomi
Yumi
Y
Yamaguchi-Kabata
Tatsuhiko
T
Tsunoda
Hironori
H
Takamura
Taiichi
T
Katayama
Ryo
R
Kimura
Kouzin
K
Kamino
Yoshio
Y
Hashizume
Masatoshi
M
Takeda
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D003433:Crosses, Genetic; D020869:Gene Expression Profiling; D006801:Humans; D016547:Kinesins; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity
D016229:Amyloid beta-Peptides; C000715688:KLC1 protein, human; C000715695:Kns2 protein, mouse; D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms; D016547:Kinesins
alternative splicing; mouse-to-human translation