Immune-Related Protein Has Opposing Actions in Early and Late Stage Alzheimer’s in Mice

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by Magdalena Kegel |

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Removing a protein involved in neuroinflammation is beneficial in early stages of Alzheimer’s disease in mice. However, in late disease stages of the disease, this action has the opposite effect, according to an animal study that helps explain contradicting results observed in earlier research.

The findings highlight the role of neuroinflammation in Alzheimer’s disease, and also demonstrate that different treatment approaches may be needed during various stages of the disease.

The study, “Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease,” was published in the Journal of Neuroscience.

The protein, TREM2 (triggering receptor expressed on myeloid cells 2), is found on brain immune cells. When it detects abnormalities in the brain, such as the presence of amyloid-beta plaque, it signals for immune cells to gather and handle the problem.

But too fierce immune activation may also be damaging for the brain and researchers discovered that by removing TREM2 from mice, the mice fared better. However, other researchers reported that TREM2 removal was hazardous for mice with Alzheimer’s disease, as the brain suffered from the abrupt influx of cells.

“Our lab and others had previously published conflicting results about how TREM2 affected pathology in Alzheimer’s mouse models. One group published data showing Alzheimer’s mice lacking TREM2 had more amyloid plaques. We previously found the opposite, that getting rid of TREM2 improved amyloid pathology,” Taylor Jay, the study’s lead author and a graduate student in the department of neurosciences at Case Western Reserve University School of Medicine, said in a press release.

“We didn’t know why we weren’t getting the same answers. And, that was just the first question we wanted to ask before we moved onto questions about exactly how TREM2 was influencing pathology,” added Jay.

The discovery of how the factor has opposite actions in early and late disease stages allows researchers to move forward and study exactly how TREM2 is involved in Alzheimer’s disease. Genetic variation in the TREM2 gene is linked to a genetic risk for Alzheimer’s.

“We demonstrate that TREM2 deficiency has opposing effects on AD-related pathologies at early and late stages of disease progression, unifying previous work in the field,” the researchers wrote.

The research team now plans to examine if their findings hold true also in other mouse models of Alzheimer’s disease.

“Our ultimate goal with these studies is to use an understanding of TREM2 function to understand the important roles that immune cells play in Alzheimer’s disease,” said Jay. “Immune cells might not be all good or all bad throughout the course of Alzheimer’s disease progression.”