Deciphering cellular transcriptional alterations in Alzheimer’s disease brains

Abstract

Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer’s disease (AD), however these findings can be confounded by cellular composition changes in bulk-tissue. To identify cell intrinsic gene expression alterations of individual cell types, we designed a bioinformatics pipeline and analyzed three AD and control bulk-RNAseq datasets of temporal and dorsolateral prefrontal cortex from 685 brain samples. We detected cell-proportion changes in AD brains that are robustly replicable across the three independently assessed cohorts. We applied three different algorithms including our in-house algorithm to identify cell intrinsic differentially expressed genes in individual cell types (CI-DEGs). We assessed the performance of all algorithms by comparison to single nucleus RNAseq data. We identified consensus CI-DEGs that are common to multiple brain regions. Despite significant overlap between consensus CI-DEGs and bulk-DEGs, many CI-DEGs were absent from bulk-DEGs. Consensus CI-DEGs and their enriched GO terms include genes and pathways previously implicated in AD or neurodegeneration, as well as novel ones. We demonstrated that the detection of CI-DEGs through computational deconvolution methods is promising and highlight remaining challenges. These findings provide novel insights into cell-intrinsic transcriptional changes of individual cell types in AD and may refine discovery and modeling of molecular targets that drive this complex disease.

Deep learning-based brain transcriptomic signatures associated with the neuropathological and clinical severity of Alzheimer’s disease

“…Among the six co-expression modules from the index genes, blue, brown, green, and turquoise modules are significantly correlated with AD phenotypical hallmarks, with the first three upregulated in the progression, while turquoise genes downregulated. Together with the cell type enrichment analysis showing the three modules are enriched in astrocytes, oligodendrocytes, and endothelial cells respectively, and turquoise module enriched in neurons, this is consistent with the results obtained by the recent work of neurodegeneration pseudotime estimation 5 and cellular composition deconvolution, 42 which shows a reduction in the neuronal populations as AD progresses, and an increase in expression associated with activation of endothelial and glial cells, as also demonstrated by the change of mean expression for the marker genes of each cell type along AD progression. Interestingly, the transcriptomic signatures obtained from our study show high similarity with the signatures obtained from a recent single-nucleus transcriptome analysis from the prefrontal cortical samples of AD patients and normal control subjects, 38 where higher proportion of endothelial nuclei were sampled and dysregulated pathways are associated with blood vessel morphogenesis, angiogenesis and antigen presentation.…”

“…fdr < 0.05, |log 2 FC| > 0.263 in the DEG analysis for ROSMAP dataset (syn8456629)), so it might not be able to capture subtle, intrinsic, and coordinated gene expression signatures due to disease pathology in the high dimensional data, especially from bulk tissues. 40,42 This is further demonstrated by the fact that neither DEGs identified by ROSMAP dataset alone (syn8456629) nor those from the AMP-AD meta-analysis (syn11914606) could fully reproduce the progressive trajectory in any of the three transcriptomic datasets, especially the external datasets when applied with the model (results not shown).…”

Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease

“…Along AD progression, the disruption of the molecular pathways of specific cell types can contribute to their observed dysfunctions. Recent studies utilized single-nucleus transcriptome analysis to investigate the transcriptomic changes in AD brains ( 12 – 14 ) and have revealed molecular alterations at the single-cell level using readily available frozen brain tissues. In particular, such studies identified the dysregulated pathways in the most predominant neural cell types, such as neurons and oligodendrocytes, in AD.…”

WITHDRAWN: Apolipoprotein E4 expressed by microglia impairs microglial functions and enhances neurotoxicity

“…Alzheimer's disease (AD) is the most common form of dementia, accounting for around 60-80% of all cases [1][2][3]. In addition to extracellular amyloid plaques and intracellular neuro brillary tangles in the brain [4][5][6], emerging evidence demonstrates the critical roles of microglia in the pathogenesis of AD [7][8][9][10][11][12]. Microglia, as the resident brain macrophage, play an important role in active immune defence in the central nervous system (CNS) [13][14][15][16].…”