Changes to energy metabolism, and signal transduction (i.e. Notch and Wnt signalling) define the brain transcriptomic differences between mutations causative for early-onset familial Alzheimer's disease or familial acne inversa in PRESENILIN 1

Background: Mutations in PRESENILIN 1 (PSEN1) which still produce a transcript encoding a full-length, but mutant protein are the most common cause of early-onset familial Alzheimer's disease (EOfAD). The only frameshift mutations found in PSEN1 causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutations, and how they lead to completely different diseases, remains largely unexplored. Objective: To identify the similarities and differences of the effects of heterozygosity for mutations in psen1 causing EOfAD (T428del) or fAI (W233fs) on the brain transcriptome of young adult zebrafish. Methods: RNA sequencing was performed with high read depth on mRNA isolated from the brains of young adult (6 month old) zebrafish arising from a single family which contained either a single, heterozygous EOfAD-like or fAI-like mutation in the endogenous psen1 gene, and their wild type siblings. Results: Both mutations appeared to downregulate genes encoding the ribosomal subunits, and upregulated genes involved in inflammation. Genes involved in energy metabolism appeared to only be affected in EOfAD-like mutants, while genes involved in Notch, Wnt and neutrophin signalling pathways were only significantly altered by the fAI-like mutation. Further investigation of direct transcriptional targets of Notch revealed an apparent increase in Notch signalling. Conclusion: We observed both common, and distinct effects on transcriptomes of the heterozygous mutants compared to their wild type siblings. The distinct effects observed may shed light to how these mutations give rise to completely different diseases. Overall design: mRNA-seq of 6 month old zebrafish whole brains from fish either heterozygous for a EOfAD-like mutation, or heterozygous for an fAI-like mutation and their wild type siblings.