Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer's Disease in Human Prefrontal...

Area of Science:

• Neuroscience
• Genomics
• Aging Research

Background:

• Aging increases Alzheimer's disease (AD) risk, exacerbating pathologies like amyloid-β (Aβ), inflammation, and oxidative stress.
• The human prefrontal cortex (PFC) is particularly vulnerable to aging and AD.
• Understanding molecular changes in the PFC is crucial for AD mechanisms and therapeutics.

Purpose of the Study:

• To create the first subcellular resolution spatial transcriptome atlas of the human PFC in normal aging (NA) and AD.
• To investigate molecular alterations across neocortical layers and cell-cell interactions during AD progression.
• To identify novel therapeutic targets for AD.

Main Methods:

• Utilized STOmics® Stereo-seq for spatial transcriptome profiling of human PFC from AD cases and controls.
• Analyzed transcriptional changes across six neocortical layers and layer-to-layer interactions.
• Performed cell-type specific gene co-expression analysis and identified regulatory factors.

Main Results:

• Revealed distinct transcriptional alterations and disrupted laminar architecture in AD PFC.
• Identified stress-responsive genes in neurons and non-neuronal cells, with diminished neuroprotective interactions in AD.
• Discovered three neuronal gene modules negatively correlated with AD progression and a novel regulator, ZNF460.

Conclusions:

• The developed spatial transcriptome atlas provides unprecedented insight into PFC molecular changes in AD.
• Diminished cellular defense and clearance mechanisms contribute to AD progression.
• ZNF460 represents a promising new therapeutic target for AD treatment.