Transcriptome Analysis Of Distinct Mouse Strains Reveals Kinesin Light Chain-1 Splicing As An Amyloid-Beta Accumulation Modifier

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (A beta). 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 A beta accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress A beta accumulation. To avoid detecting secondarily affected genes by A beta, we used non-Tg mice in the absence of A beta 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 A beta modifier, indicating a role for intracellular trafficking in A beta accumulation. A beta 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 A beta, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of A beta 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.