Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics

Area of Science:

• Neuroscience
• Pathology
• Genomics

Background:

• Alzheimer's Disease (AD) is characterized by amyloid-beta (Aβ) plaques and glial activation.
• The precise interaction between Aβ plaques and glial cells in the human brain remains unclear.

Purpose of the Study:

• To investigate the transcriptomic profiles of glial cells surrounding Aβ plaques in human AD brains.
• To elucidate the role of glial responses in Aβ-mediated neurodegeneration and synaptic loss.

Main Methods:

• Spatial transcriptomics (ST) and immunohistochemistry (IHC) were applied to postmortem human brain sections.
• Coupling ST with adjacent-section IHC allowed for detailed analysis of Aβ, glial cells (GFAP, IBA1), and neuronal markers.

Main Results:

• Low Aβ areas showed transcriptomic signs of greater neuronal loss, while high-glia areas indicated increased inflammation and neurodegeneration.
• Glial responses around plaques mirrored known mouse gene modules (PIG, OLIG, DAM, DAA) and human microglia states.
• Aβ exposure in iPSC-derived microglia-like cells mimicked the observed glial response in AD brains.

Conclusions:

• Microglia response to Aβ oligomers likely initiates glial activation in plaque-glia niches, exacerbating synaptic and neuronal loss.
• The study provides a foundation for understanding pathological heterogeneity and causal effects in neurodegenerative diseases.