Transcriptome analysis of early-onset familial Alzheimer’s disease and Sanfilippo syndrome zebrafish models reveals commonalities in disease mechanisms

Abstract

AbstractBackgroundAutosomal recessive inheritance of Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) causes childhood dementia, while Alzheimer’s disease is the most common type of adult-onset dementia. There are no approved treatments for Sanfilippo patients, and few options exist for those with Alzheimer’s disease. Increasing evidence suggests commonalities in the disease processes. However, a direct comparison of animal models with the two disorders has never been performed.MethodWe used RNA-seq to compare the transcriptome of zebrafish with early-onset familial Alzheimer’s disease (EOfAD,psen1Q96_K97del/+), or MPS IIIB (nagluA603fs/A603fs) with their wild type siblings at 7 days post fertilisation and at 6 months of age (n = 8 fish per genotype).ResultsDifferential gene expression and pathway analysis at each age revealed substantially more differentially expressed genes and pathways in MPS IIIB zebrafish relative to wild type than in the EOfAD-like zebrafish, consistent with MPS IIIB being a more severe, rapidly progressing and earlier onset form of dementia. Similar changes in gene expression were detected between the models in the extracellular matrix receptor interaction pathway in zebrafish larvae, and oxidative phosphorylation, ribosome and lysosome pathways in 6-month-old adult zebrafish brains. Cell type-specific changes in gene expression were detected for MPS IIIB zebrafish brains at 6 months of age, possibly reflecting altered proportions of oligodendrocytes, neural stem cells and inflammatory cells.ConclusionsOur transcriptome analyses have illuminated possible shared disease mechanisms between EOfAD due toPSEN1mutations and MPS IIIB. Future work will investigate the nature of these commonalities.