Map of 832 505 brain immune cells helps distinguish aging from Alzheimer's pathology
Map of 832 505 brain immune cells helps distinguish aging from Alzheimer's pathology
On August 11, Nature Genetics published a study of 832 505 myeloid cells from the prefrontal cortex of 1 607 donors. Based on gene activity, the authors identified six broad classes and 13 subtypes, examined their associations with age and the severity of Alzheimer's disease pathology, and made the data, analyses, and code available for independent verification.
Microglia are immune cells in the brain, while perivascular macrophages function along blood vessel walls. In the aging human brain, genetic markers have already shown that some cells resembling microglia are replenished by descendants of bone marrow cells. Age, disease, and sample preparation can therefore alter the signal at the same time. An averaged measurement may confuse a change in cellular composition with a change in cellular function.
The researchers compared two large datasets: cells isolated after autopsy and cell nuclei obtained from frozen tissue. They then identified all 13 subtypes in independent biopsies of living tissue from 25 donors. Spatial analysis confirmed that some of these cells were located near blood vessels. The resulting map therefore provides a basis for comparing specific cellular states, rather than merely listing genes.
One subtype stood out: microglia with high activity of the GPNMB gene. Its proportion increased with Alzheimer's pathology and was associated with the combined inherited risk of the disease. Gene regulation analysis pointed to MITF, a transcription factor, which is a protein that controls the activity of other genes. In a human microglial cell line, the researchers used CRISPR activation, a method for selectively switching on a gene, to activate MITF and GPNMB separately. After normalization for cell density, these cells showed greater uptake of β-amyloid, the protein that forms deposits in Alzheimer's disease, and dying neurons. The authors also examined the role of TREM2, a receptor on the surface of microglia that is associated with maintaining this state, using microglial models derived from reprogrammed human cells and a mouse model.
The dataset available through the AD Knowledge Portal gives other groups access to the same data so that they can verify these comparisons and conduct new experiments on specific cellular states.