Post by Thomas Brown

What's the science?

Alzheimer’s disease (AD) represents one of the greatest challenges faced by modern science, however, little is known about the mechanisms behind the disease. Many recent studies have drawn attention to the role of resident immune cells within the brain, known as microglia, in Alzheimer’s disease. A mutation within TREM2, a gene associated with microgliosis and increased AD risk, is believed to cause a ‘loss of function’ of one of its two alleles. This week in PNAS, Sayed et al. recreated this loss of TREM2 activity; in one, or both alleles of the gene, to test the effect on microglial function.

How did they do it?

The authors utilized in vivo imaging to quantify microglial activity. Firstly, adult 9-14 month old mice were divided into three groups; wild-type (WT) (TREM2+/+), single-allele knockouts (TREM2 haploinsufficient mice: TREM2+/-,) and full knockouts (TREM2-/-). These mice were then crossed with a mouse with a green fluorescent protein marker linked with a receptor commonly found on microglia, ensuring that microglia would glow and allowing for live visualization. Through utilization of a microscope attached to the head of the mouse, the authors were able to see the microglial response to injury. The brains were then lesioned with a laser and the morphology of the microglia was inspected following the lesion. Additionally, they also analyzed the expression of different microglial genes using quantitative real time polymerase chain reaction. Finally, the expression of tau aggregates (a protein that aggregates in the brain in Alzheimer’s disease) was measured in TREM2+/+, TREM2+/-, and TREM2-/- mice genetically modified to express human tau, using an antibody that binds to tau.

What did they find?

Microglial response to injury in TREM2+/- mice was slow, and these microglia extended less processes than wild-type controls (TREM-/- mice). This indicates that the brains of TREM2+/- mice were less responsive to injury. Additionally, gene expression of IL-1α, IL-1β and TNF-α (inflammatory markers) was elevated in TREM2+/- mice. The TREM2 haploinsufficient mice (with partial loss of TREM2) who were also expressing human tau demonstrated increased tau pathology, however, the full TREM2 knockout mice did not. The impaired microglial response to injury, increased expression of inflammatory markers, as well as an increase in tau levels, suggest that the haploinsufficient TREM2 mice had an AD-like pathology.