Abstract
The detailed characteristics of neuronal cell populations in Alzheimer’s disease (AD) using single-cell RNA sequencing have not been fully elucidated. To explore the characterization of neuronal cell populations in AD, this study utilized the publicly available single-nucleus RNA-sequencing datasets in the transgenic model of 5X familial Alzheimer’s disease (5XFAD) and wild-type mice to reveal an AD-associated excitatory neuron population (C3:Ex.Neuron). The relative abundance of C3:Ex.Neuron increased at 1.5 months and peaked at 4.7 months in AD mice. Functional pathways analyses showed that the pathways positively related to neurodegenerative disease progression were downregulated in the C3:Ex.Neuron at 1.5 months in AD mice. Based on the differentially expressed genes among the C3:Ex.Neuron, four subtypes (C3.1–4) were identified, which exhibited distinct abundance regulatory patterns during the development of AD. Among these subtypes, the C3.1 neurons [marked by netrin G1 (Ntng1)] exhibited a similar regulatory pattern as the C3:Ex.Neuron in abundance during the development of AD. In addition, our gene set variation analysis (GSEA) showed that the C3.1 neurons, instead of other subtypes of the C3:Ex.Neuron, possessed downregulated AD pathways at an early stage (1.5 months) of AD mice. Collectively, our results identified a previously unidentified subset of excitatory neurons and provide a potential application of these neurons to modulate the disease susceptibility.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease, characterized by progressive cognitive decline, and first described by Alois Alzheimer in the early twentieth century (Ballard et al, 2011; Bondi et al, 2017)
Two representative genes for each cell population were showed in a violin chart (Figure 1B), and the expression distribution of classic marker genes was shown by the Uniform Manifold Approximation and Projection (UMAP) diagram (Figure 2C and Supplementary Figure 2B)
The study on the pathogenic mechanism of AD is of great significance for its treatment, and single-cell sequencing-based analysis will provide novel insights of how the individual cell populations contribute to AD and the previously unidentified cellular mechanisms
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease, characterized by progressive cognitive decline, and first described by Alois Alzheimer in the early twentieth century (Ballard et al, 2011; Bondi et al, 2017). 5X familial Alzheimer’s disease (5XFAD) model mice with mutated amyloid beta precursor protein (APP) and presenilin (PSEN1 and PSEN2) genes are widely used in AD studies, as they quickly simulate the main pathological features of amyloid protein (Oakley et al, 2006). Analysis of the olfactory bulb single-cell atlas in patients with AD revealed that a set of transcriptional factors (TFs) from specific cell populations is the driving factor that mediates the transition of AD (Grubman et al, 2019). Despite these advances, the detailed characteristics of neuronal cell populations during AD development are yet to be fully elucidated
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