Stress-Responsive Transcriptomic Signatures in Human iPSC-Derived Microglia Reveal Links to Alzheimer's Disease Risk...

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Cellular stress responses are vital for homeostasis, particularly in the central nervous system where microglia act as immune responders.
• The specific molecular pathways microglia engage under different stress conditions and their effect on cell survival are not fully understood.

Purpose of the Study:

• To investigate stress responses in human induced pluripotent stem cell-derived microglia-like cells (iPSC-microglia) when exposed to amyloid beta (Aβ) and lipopolysaccharide (LPS).
• To identify genetic factors influencing microglial survival during stress using a CRISPR interference screen targeting Alzheimer's disease-associated genes.

Main Methods:

• Utilized single-cell RNA sequencing to map transcriptional programs in iPSC-microglia under Aβ and LPS stress.
• Benchmarked these transcriptional states against existing mouse and human microglial datasets.
• Conducted a pooled CRISPR interference screen to identify genes affecting microglial survival.

Main Results:

• Amyloid beta and LPS induced distinct yet partially overlapping transcriptional responses in iPSC-microglia.
• LPS triggered broader inflammatory activation and higher cell death rates compared to Aβ.
• A subset of stress-activated genes overlapped with Alzheimer's disease risk genes and genes identified in the survival screen.

Conclusions:

• Human iPSC-derived microglia-like cells effectively model in vivo-like stress responses.
• Disease-associated microglial genes may play a role in stress adaptation and cellular fitness.
• Findings provide a foundation for enhancing microglial resilience in neurodegenerative diseases by linking stress sensing, survival, and disease-associated gene networks.