Abstract
BackgroundAlzheimer's disease (AD) is a pervasive age-related and highly heritable neurodegenerative disorder but has no effective therapy. The complex cellular microenvironment in the AD brain impedes our understanding of pathogenesis. Thus, a comprehensive investigation of cell type-specific responses in AD is crucial to provide precise molecular and cellular targets for therapeutic development.MethodsHere, we integrated analyzed 4,441 differentially expressed genes (DEGs) that were identified from 263,370 single-cells in cortex samples by single-nucleus RNA sequencing (snRNA-seq) between 42 AD-pathology subjects and 39 normal controls within 3 studies. DEGs were analyzed in microglia, astrocytes, oligodendrocytes, excitatory neurons, inhibitory neurons, and endothelial cells, respectively. In each cell type, we identified both common DEGs which were observed in all 3 studies, and overlapping DEGs which have been seen in at least 2 studies. Firstly, we showed the common DEGs expression and explained the biological functions by comparing with existing literature or multil-omics signaling pathways knowledgebase. We then determined the significant modules and hub genes, and explored the biological processes using the overlapping DEGs. Finally, we identified the common and distinct dysregulated pathways using overall DEGs and overlapping DEGs in a cell type-specific manner.ResultsUp-regulated LINGO1 has been seen in both oligodendrocytes and excitatory neurons across 3 studies. Interestingly, genes enriched in the mitochondrial module were up-regulated across all cell types, which indicates mitochondrial dysfunction in the AD brain. The estrogen signaling pathway seems to be the most common pathway that is disrupted in AD.ConclusionTogether, these analyses provide detailed information of cell type-specific and overall transcriptional changes and pathways underlying the human AD-pathology. These findings may provide important insights for drug development to tackle this disease.
Highlights
Alzheimer’s disease (AD) is a pervasive age-related and highly heritable neurodegenerative disorder but has no effective therapy
Energy supply, and oxidative stress, as well as reduced protein degradation in microglia Human genetic studies pointed out a key role of microglia in the pathogenesis of AD [13]
These findings indicate that the dysregulated immune response and the involvement of the estrogen signaling pathway may be the common characteristic of microglia in AD
Summary
Alzheimer’s disease (AD) is a pervasive age-related and highly heritable neurodegenerative disorder but has no effective therapy. The complex cellular microenvironment in the AD brain impedes our understanding of pathogenesis. A comprehensive investigation of cell type-specific responses in AD is crucial to provide precise molecular and cellular targets for therapeutic development. Alzheimer’s disease (AD) is the most common form of dementia characterized by the accumulation of extracellular amyloid-β (Aβ) and neurofibrillary tangles, and progressive synaptic and neuronal dysfunction and degeneration [1,2,3]. AD pathogenesis is not restricted to neurons and increasing evidence suggests that multiple cell type interactions in the brain promote AD development [4,5,6,7,8]. It’s important to clearly understand how different cell types contribute to AD progression and outcome. A recent in vivo study showed that astrocytes are involved in the engulfment of apoptotic neurons to maintain brain homeostasis [21], which may play an important role in the AD brain
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