Network analysis reveals strain-dependent response to misfolded tau aggregates

Mouse genetic backgrounds have been shown to modulate amyloid accumulation and propagation of tau aggregates. Previous research into these effects has highlighted the importance of studying the impact of genetic heterogeneity on modeling Alzheimers disease. However, it is unknown what mechanisms underly these effects of genetic background on modeling Alzheimers disease, specifically tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT (P301L). To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of 6-month-old C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n=64). We also measured tau seeding activity in the cortex of these mice. We identified three gene signatures: core transcriptional signature, unique signature for each wild-derived genetic background, and tau seeding-associated signature. Our data suggest that microglial response to tau seeds is elevated in CAST/EiJ and PWK/PhJ mice. Together, our study provides the first evidence that mouse genetic context influences the seeding of tau. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/526029v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1c99217org.highwire.dtl.DTLVardef@965522org.highwire.dtl.DTLVardef@1af4105org.highwire.dtl.DTLVardef@d5ea98_HPS_FORMAT_FIGEXP M_FIG C_FIG SUMMARYSeeding of tau predates the phosphorylation and spreading of tau aggregates. Acri and colleagues report transcriptomic responses to tau and elevated tau seeds in wild-derived mice. This paper creates a rich resource by combining genetics, tau biosensor assays, and transcriptomics.