Characterizing dysregulations via cell-cell communications in Alzheimer's brains using single-cell transcriptomes

Area of Science:

• Neuroscience
• Genomics
• Cell Biology

Background:

• Alzheimer's disease (AD) affects 44 million globally, causing cognitive decline.
• Single-cell sequencing offers high-resolution gene expression analysis.
• Understanding cell-to-cell communication in the brain's microenvironment is crucial for AD research.

Purpose of the Study:

• Investigate cell-to-cell communication networks in the human prefrontal cortex.
• Compare communication patterns in healthy brains versus Alzheimer's disease (AD) brains.
• Identify specific signaling pathway dysregulations and their links to AD risk genes.

Main Methods:

• Utilized large-scale, single-nucleus RNA sequencing (snRNA-seq) data from the human prefrontal cortex.
• Processed snRNA-seq data with strict quality controls and cell type annotation.
• Constructed a cell-to-cell communication network using ligand and receptor gene expression.

Main Results:

• Normal brains show overlapping signaling networks between related cell types; AD brains exhibit mixed cell types and signaling.
• Excitatory neurons in AD increase communication with inhibitory neurons; other cells decrease communication.
• Canonical pathways (CSF, TGFβ, CX3C) are dysregulated in AD, particularly involving microglia/PVM and endothelial-to-neuronal signaling (WNT pathway).
• Extracellular AD risk genes (APP, APOE, PSEN1) connect to intracellular risk genes (TREM2, ABCA1, APP) in astrocyte/microglia-to-neuron communication.

Conclusions:

• Cellular signaling in AD is regulated in a cell-type-specific manner.
• Dysregulation of extracellular signaling genes is linked to intracellular AD risk genes.
• This study provides a mechanistic, intra- and inter-cellular perspective on Alzheimer's disease.