Alzheimer’s disease (AD) is the leading cause of dementia in aging individuals. Yet, the pathophysiological processes involved in AD onset and progression are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain could contribute for a better understanding of the AD pathology. In this work, we probed the differential expression of genes in different brain regions of healthy and AD adult subjects using data from three large transcriptomic studies: Mayo Clinic, Mount Sinai Brain Bank (MSBB), and ROSMAP. Using a combination of differential expression of gene and isoform switch analyses, we provide a detailed landscape of gene expression alterations in the temporal and frontal lobes, harboring brain areas affected at early and late stages of the AD pathology, respectively. Next, we took advantage of an indirect approach to assign the complex gene expression changes revealed in bulk RNAseq to individual cell types/subtypes of the adult brain. This strategy allowed us to identify previously overlooked gene expression changes in the brain of AD patients. Among these alterations, we show isoform switches in the AD causal gene amyloid-beta precursor protein (APP) and the risk gene bridging integrator 1 (BIN1), which could have important functional consequences in neuronal cells. Altogether, our work proposes a novel integrative strategy to analyze RNAseq data in AD and other neurodegenerative diseases based on both gene/transcript expression and regional/cell-type specificities.

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.

Background Alzheimer’s disease (AD) is the leading cause of dementia in aging individuals. Several studies have shown that 60‐80% of late‐onset AD attributable risk has an important genetic component. However, a comprehensive overview of gene expression alterations in the diseased brain remains elusive. Method In this work, we compared the differential expression of genes in different regions (temporal and frontal lobes) of the brain of healthy and AD adult subjects from three large datasets: MAYO Clinic; Mount Sinai Brain Bank (MSBB) and ROSMAP. We also used isoform switch analysis to identify genes with altered transcript usage. Finally, we assigned altered genes to specific cell types of the adult brain and evaluate the expression of AD risk genes previously identified in pan‐genomic association studies. Result We show that gene expression is dramatically altered in the temporal lobe (TL), but not in the frontal lobe (FL), suggesting regional specificities in transcriptional alterations. Moreover, we show that a large set of genes without alteration in the classical differential expression (DEG) analysis do have alterations in the transcript usage ratio in AD. Ontology analysis for genes with differential transcript usage (gDTUs) show enrichment for key biological processes associated with AD pathology, which are not observed for DEGs only. Using single‐cell RNAseq data, we are able to assign DEGs and gDTUs to individual cell types of the adult brain and show that genes associated with synaptic transmission are mostly affected in GABAergic neurons. Lastly, we show that 52 out of 116 putative AD risk factors expressed in neural cells, microglia or endothelial cells of the adult human brain are differentially expressed in the TL, whereas only 13 are altered in the FL of AD patients. Among those altered genes, we detect an increased expression of APP isoforms containing the Kunitz protease inhibitor (KPI) domain, which is associated with plaque deposition. Conclusion Altogether, our work proposes a novel integrative strategy to analyse transcriptional data in AD based on both gene/transcript expression and cell‐type specificities and reveal an alteration of APP expression that could contribute to explain the increased production of Abeta 1‐42 in the AD brain.

Background Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade hypothesis postulates that deposition of Aβ peptides is the causative agent of AD pathology, but we still lack comprehensive understanding about the molecular mechanisms connecting Aβ peptides to neuronal dysfunctions in AD. In this work, we investigated the early effects of Aβ peptides accumulation on the functional properties and gene expression profiles of human-induced neurons (hiNs). Methods We exposed 6-weeks-old hiNs to low concentrations of cell-secreted Aβ oligomers or synthetic Aβ and performed time-lapse time microscopy to detect fast calcium transients as an indirect readout of neuronal electrical function. Next, we used single-nucleus RNA sequencing (snRNA-seq) to probe early Aβ-mediated gene expression alterations in hiNs and human-induced astrocytes (hiAs). Lastly, we leveraged snRNA-seq data to identify patterns of intercellular communication modulated by Aβ oligomers. Results We show that hiNs acutely exposed to low concentrations of both cell-secreted Aβ peptides or synthetic Aβ1−42 exhibit alterations in the frequency of calcium transients suggestive of increased neuronal excitability. We also show that cell-secreted Aβ up-regulates the expression of several synaptic-related genes and down-regulates the expression of genes associated with metabolic stress mainly in glutamatergic neurons and to a lesser degree in GABAergic neurons and astrocytes. These neuronal alterations correlate with activation of SEMA5, EPHA and NECTIN signaling pathways, which are important regulators of synaptic plasticity. Conclusions Our findings indicate that slight elevations in Aβ concentrations are sufficient to elicit transcriptional changes in human neurons with long lasting consequences to neural network activity and suggest that at least part of the effects of Aβ on synapses might be mediated by semaphorin, ephrin and nectin signaling pathways.