Análises de redes modulares de co-expressão gênica revelam vias importantes na doença de Alzheimer e paralisia supranuclear progressiva
The incidence of neurodegenerative diseases leading to impairment of cognitive functions and dementia have increased in recent years, mainly because of enhanced longevity in the population worldwide. Understanding the onset and progression of these pathologies can help to develop preventive and disease-modifying treatments for these diseases. In this work, using RNA-seq data obtained from two brain regions (temporal cortex and cerebellum) of human patients diagnosed with neurodegenerative diseases (Alzheimer or Progressive Supranuclear Palsy) and two animal models, 5XFAD of amyloidopathy and TauD35 of tauopathy, we performed an integrative analysis at the gene/transcript level combined with a co-expression analysis to identify similarities and discrepancies in the biological processes affected by these two diseases. So that we could compare the different data, we used the only common variable in all datasets: age of death. Thus, we divided the human data into 3 groups: A (70-80), B (81-89) and C (90+); and animals in groups of 4 months, 12 months, 17 months and 18 months. The results of the transcriptional analysis showed that gene expression alterations associated with immune-inflammatory alterations are present in AD only in the temporal cortex and not in the cerebellum, and that alteration related to synaptic transmission occurs late (groups B and C), and are found only when we use genes with isoform switches in the analysis of functional enrichment in conjunction with differentially expressed genes. In PSP, all changes associated with immune-inflammatory responses and synaptic transmission are found exclusively in temporal cortex data; however, all changes are specific for group A. In animal models, changes in 5XFAD are similar to those found in AD human brains, with gene expression alterations associated with the immune-inflammatory response present early (4 months) and synaptic terms only at late pathological stages (18 months). In TauD35 mice, this pattern is inverted, with gene expression changes associated with immune-inflammatory response identified only late (17-month group), whereas those associated with synapses could be identified early (4-month group). In addition to these results, we observed that changes in isoforms (gDTUS) are present almost exclusively in humans, and especially in AD. To refine our results, we used a co-expression approach and identified modules with specific expression and gene signatures. In AD, modules involving synapses did not differ from control, however, modules related to immune-inflammatory response, extracellular matrix and growth factor response were more active in individuals with AD. In PSP, modules with synaptic activity showed greater activity compared to control, while those related to immune response had a lower activity. To confirm the genetic identity of these modules, we also mapped module-specific genes to different cell types of the brain using single-cell RNA-seq data. This analysis revealed a correspondence between modules related to the immune-inflammatory response with microglial cells and, to a lesser extent in AD, astrocytes, synaptic cells with glutamatergic neurons and myelination with oligodendrocytes. Finally, we show that genes identified as risk factors for AD or PSP are present in specific co-expression. Together, these results suggest that in the amyloidopathy model and in AD, alterations in synaptic signaling form a positive feedback with the immune inflammatory response, the latter being the first; while in the model of tauopathy and PSP, the effects on inflammation are secondary to synaptic changes.
Doença de Alzheimer (AD), Paralisia supranuclear progressiva (PSP), 5XFAD, TauD35, Módulos
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Universidade Federal do Rio Grande do Norte