Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states
Microglia are central mediators of Alzheimers disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk,…
Microglia play a crucial role in the development of Alzheimer's disease (AD), but the specific mechanisms and potential treatments for AD-associated microglial states remain unclear. Researchers have now analyzed single-nucleus transcriptomic data from AD patients, uncovering a new type of microglia called disease- and lipid-associated microglia (DLaM). This population is enriched in AD patients and is associated with genetic risk factors, brain damage, and cognitive decline.
To simulate DLaM in a lab setting, scientists tested various treatments on human-induced pluripotent stem cell (hiPSC)-derived microglia. They discovered that ferric ammonium citrate (FAC) effectively mimicked the DLaM state, leading to lipid buildup, lysosomal dysfunction, and decreased ability to clear a toxic protein called amyloid-beta (Aβ).
To reverse this state, the researchers used a method called transcriptomics-based state-reversion screening, which identified a drug called LY2090314 as a promising modifier. LY2090314 helped restore normal microglial function and switched the cells into a different metabolic state that was less harmful to the brain. These findings offer a new approach for identifying potential treatments for Alzheimer's disease based on the specific state of the microglia involved.
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