Inflammatory Effects of Trem1 are Associated with Risk of Developing Alzheimer’s Disease
Post by Shireen Parimoo
The takeaway
Trem1 is a receptor protein found in macrophages – a type of white blood cell – that increases in older age and has pro-inflammatory effects. Deletion of Trem1 reduces inflammation by increasing mitochondrial metabolism and rescues cognitive deficits associated with aging and Alzheimer’s disease, such as memory loss.
What's the science?
Myeloid cells like microglia and macrophages are critical for optimal brain and immune functioning. Alzheimer’s disease (AD) is characterized by pathology including the accumulation of amyloid protein and neurofibrillary tangles. Research has identified many families of genes that are associated with an increased risk of developing Alzheimer’s disease (AD). In aging mice, a receptor expressed on myeloid cells-1 (Trem1) has pro-inflammatory effects that lead to higher rates of cognitive decline and greater amyloid accumulation. However, the exact role of Trem1 in AD is presently unclear. This week in Nature Neuroscience, Wilson and colleagues investigated the cellular mechanisms by which Trem1 regulates myeloid cell functioning and its effects on memory in typical aging and AD.
How did they do it?
The authors performed a series of experiments on several mouse models. The first included old and young wildtype mice and mice with deletion of both Trem1 alleles (Trem1-/-), which allowed them to identify the baseline effects of Trem1 deletion on myeloid cell functioning. Here, flow cytometry was used to look at Trem1 expression in myeloid cells of wildtype and mice with deleted Trem1 alleles. Next, inflammatory markers in plasma, peripheral macrophages, and the brain were quantified and compared to performance on spatial and object recognition memory tasks. The authors then used RNA sequencing to compare the differences in microglial and macrophage gene expression between the groups. Finally, as energy metabolism is important for regulating inflammatory responses, they investigated the effects of Trem1 deletion on macrophage metabolism by characterizing the expression of mitochondrial genes in the mouse models.
The second group consisted of mouse models of AD (i) without Trem1 deletion, (ii) with deletion of a single Trem1 allele, and (iii) with deletion of both Trem1 alleles. These AD mouse models enabled the authors to determine how Trem1 deletion affects the cellular responses of microglia and macrophages to amyloid burden and its effect on memory. As before, they measured Trem1 expression, inflammatory responses, memory performance, and mitochondrial metabolism. Finally, to determine whether Trem1 is implicated in human AD, the authors used human frontal cortex tissue from controls and patients with AD to quantify Trem1 levels and to examine the relationship between Trem1 and disease severity.
What did they find?
Older wildtype mice had elevated Trem1 expression when compared to younger wildtype mice, as well as higher levels of inflammatory markers in plasma. Mice with Trem1 deletion, however, showed similar levels of plasma and brain inflammatory proteins as the younger mice. Anti-inflammatory markers in macrophages were lower in older than younger mice while pro-inflammatory markers showed the opposite pattern. Within the older group, mice with the deletion of both Trem1 alleles had higher anti-inflammatory and lower pro-inflammatory markers, better spatial and object memory performance, and different gene expression profiles of proteins associated with mitochondrial metabolism and inflammatory regulation in peripheral macrophages compared to the wildtype mice. Together, these results suggest that in typical aging, Trem1 expression negatively affects memory through pro-inflammatory mechanisms while Trem1 deficiency has neuroprotective effects.
Trem1 expression was higher in post-mortem brains of humans who had AD than those who didn’t, and elevated levels of Trem1 were associated with more advanced stages of AD. In mouse models of AD, mice with and without Trem1 deficiency had similar amyloid burden as well as similar levels of Trem1 in microglia. Compared to AD mice with both Trem1 alleles deleted, the deletion of only a single Trem1 allele rescued memory performance. Trem1 deletion in AD was also associated with lower inflammatory markers in the blood, indicating that the increased presence of Trem1 in aging has adverse effects on cognition due to increased inflammatory responses in AD, irrespective of amyloid burden.
What's the impact?
This study is the first to demonstrate the role of Trem1 signaling in the risk of developing Alzheimer’s disease. The finding that Trem1 expression increases with age and promotes inflammation via metabolic pathways provides an avenue for future research to develop treatments targeting those specific pathways.