Analysis of modular gene co-expression networks reveals molecular pathways underlying Alzheimer's disease and progressive supranuclear palsy

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. Using a systems biology approach to uncover biological processes associated with gene expression alterations, we could pinpoint processes more strongly associated with tauopathy/PSP and amyloidopathy/AD. We show that gene expression alterations related to immune-inflammatory responses preponderate in younger, whereas those associated to synaptic transmission are mainly observed in older AD patients. In PSP, however, changes associated with immune-inflammatory responses and synaptic transmission overlap. 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. Altogether, this work contributes to unravel the potential biological processes affected by amyloid versus tau pathology and how they could contribute to the pathogenesis of AD and PSP.

Automated summary

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. In this study, the researchers compared gene expression alterations in the brains of AD and PSP patients, as well as animal models of amyloidopathy and tauopathy, to uncover the biological processes associated with these diseases. They found that immune-inflammatory responses were more prevalent in younger AD patients, while changes related to immune-inflammatory responses and synaptic transmission overlapped in PSP patients. Gene expression alterations related to RNA splicing were highly prevalent in AD, but not in PSP or animal models. The study also identified genetic risk factors for AD and PSP in cell-type specific co-expression modules.