A comprehensive understanding of the pathological mechanisms involved at different stages of neurodegenerative diseases is key for the advance of preventive and disease-modifying treatments. Gene expression alterations in the diseased brain is a potential source of information about biological processes affected by pathology. In this work, we performed a systematic comparison of gene expression alterations in the brains of human patients diagnosed with Alzheimer's disease (AD) or Progressive Supranuclear Palsy (PSP) and animal models of amyloidopathy and tauopathy. Comparisons of gene/transcript expression alterations in different brain regions of AD and PSP patients at different stages of pathology using system biology approaches allowed us to pinpoint major biological processes involved in the pathogenesis of these diseases. Notably, our data reveal that gene expression alterations related to immune-inflammatory responses preponderate early, whereas those associated to synaptic transmission are mainly observed at mid-to-late pathological states in AD brains. In PSP, however, changes associated with immune-inflammatory responses and synaptic transmission overlap at early stages of disease. These two different patterns observed in AD and PSP brains are fairly recapitulated in animal models of amyloidopathy and tauopathy, respectively. Moreover, in AD, but not PSP or animal models, gene expression alterations related to RNA splicing are highly prevalent, whereas those associated with myelination are enriched both in AD and PSP, but not in animal models. Finally, we identify 12 AD and 4 PSP genetic risk factors in cell-type specific co-expression modules, thus contributing to unveil the possible role of these genes to pathogenesis.
Analysis of modular gene co-expression networks reveals molecular pathways underlying Alzheimer's disease and progressive supranuclear palsy
