Transcriptional Signatures of Progressive Neuropathology in Transgenic Models of Tau and Amyloid Pathology

Abstract

The onset and progression of Alzheimer’s disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and the accumulation of β-amyloid (Aβ) in the neocortex. Despite recent success in identifying genetic risk factors for AD, the transcriptional mechanisms involved in disease progression are not fully understood. We used transgenic mice harbouring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the development of both tau and amyloid pathology. Using highly-parallel RNA sequencing we profiled transcriptional variation in the entorhinal cortex at four time points identifying robust genotype-associated differences in entorhinal cortex gene expression in both models. We quantified neuropathological burden across multiple brain regions in the same individual mice, identifying widespread changes in gene expression paralleling the development of tau pathology in rTg4510 mice. There was a striking overlap between differentially expressed transcripts and genes associated with familial AD from genetic studies of human patients, and genes annotated to both common and rare variants identified in genome-wide association and exome-sequencing studies of late-onset sporadic AD. Systems-level analyses identified discrete co-expression networks associated with the progressive accumulation of tau, with these enriched for genes and pathways previously implicated in the neuro-immunological and neurodegenerative processes driving AD pathology. Finally, we report a highly-significant overlap between tau-associated networks and AD-associated co-expression modules identified in analyses of post-mortem human cortex. This study represents the most systematic analysis of progressive changes in gene expression in mouse models of AD pathology and the first to focus specifically on the entorhinal cortex, a key region affected early in human Alzheimer’s disease (AD). Our data provide further strong for an immune-response component in the accumulation of tau, and reveal novel molecular pathways associated with the progression of AD neuropathology.