Andreasson KI, Wilson EN, Wang C, Xin M, Panchal M, Rabinowitz JD, Minhas PS, Swarovski MS, Benitez JA, Durairaj AS, Chaney A, Iweka CA, Buckwalter MS, Ennerfelt HE, Umans J, Huang J, Zera KA, McReynolds MR, Greicius MD, James ML, Mehta SS, LeGuen Y, Tan YJ, Zuckerman AJ, Blacher E, Gauba E, Serrano GE, Cropper H, Jain P, Liu Q. TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease models. 2024 Mar 11 10.1101/2024.03.05.583562 (version 1) bioRxiv.
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Columbia University
Columbia University
This paper highlights, and raises questions about, potential crosstalk between the peripheral immune system and central nervous system microglia and how this communication could be a powerful modulator of neurodegeneration. While the authors found very small numbers of TREM1+ myeloid cells in the mouse brain, concluding that peripheral TREM1 drives the phenotype, TREM1 KO microglia are resistant to bioenergetic changes caused by amyloid oligomer stimulation in vitro. It is important to note that once microglia are removed from their environment, they change their transcriptional profile to more resemble a non-specialized myeloid cell.
Linking TREM1 to microglial bioenergetics and to myeloid cell metabolism in general is very exciting. It opens a new avenue of potential therapeutic approaches for Alzheimer’s disease. The microglial bioenergetic experiments highlight the role these cells play in aging, and distinctly in diseases of aging, and emphasize these cells as major contributors to brain homeostasis. More work will be needed to determine what the contribution is of peripheral TREM1 and microglial TREM1 to the cognitive and behavioral phenotypes they observe in aged and APP mutant mice.
It was exciting to see a population of TREM1-positive microglia in the brains of these mice. Interestingly, this population grows in aged mice. Most surprising was the robust staining and immunoblotting of human TREM1 in the brains of both control and AD patients, suggesting the protein level is much higher than would be suspected by RNA-sequencing studies. Either the protein and RNA levels are not well correlated or indeed peripheral TREM1 is entering the brain and binding microglia specifically in aged and Alzheimer’s individuals. It was also exciting to see that their data suggest metabolic changes could be a driver of microglia phenotype and function. Intriguingly, they report increased brain glucose metabolism in the APPSwe model, while in their aging model and in human Alzheimer’s patients, there is a decrease in brain glucose metabolism. This speaks to both the difference between aging and diseases of aging, as well as what models should be used for studying neurodegeneration as it becomes clear microglial metabolism is a key component in diseases of aging.
At first glance, these results might appear to be counter to our findings that human monocytes decrease surface expression of TREM1 and have a reduced ratio of TREM1 to TREM2 on an AD pathology risk allele background (Chan et al., 2015). However, TREM1, like TREM2, exists as both a membrane-bound signaling molecule and a soluble receptor. Wilson et al. found that increased plasma levels of soluble TREM1 correlated with increased AD risk while the opposite was true for sTREM2. It is unclear if the sTREM1 comes from cleaved membrane-bound TREM1 or is a separate isoform, but there is potentially an inverse relationship between the soluble and membrane-bound forms. More work needs to be done to understand the function of sTREM1 compared to membrane-bound TREM1. Specifically, to determine if sTREM1 blocks membrane-bound TREM1 function as has been suggested (reviewed by Zhang et al., 2022).
References:
Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR, Cuerdon NE, Ryan KJ, Johnson KA, Schneider JA, Bennett DA, Chibnik LB, Sperling RA, Bradshaw EM, De Jager PL. CD33 modulates TREM2: convergence of Alzheimer loci. Nat Neurosci. 2015 Nov;18(11):1556-8. Epub 2015 Sep 28 PubMed.
Zhang C, Kan X, Zhang B, Ni H, Shao J. The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases. Mol Brain. 2022 Oct 22;15(1):84. PubMed.
View all comments by Kirstin TamucciWeizmann Institute of Science
The paper by Wilson et al. is extremely timely and important. It attributes a key role to myeloid cells in coping with aging in general, and age-related neurodegenerative diseases in particular, with an emphasis on Alzheimer’s disease, focusing on triggering receptor expressed on myeloid cells 1 (TREM1).
The role of myeloid cells, including blood-borne and resident microglia, in AD has been extensively explored, with a focus on TREM2. In this study, the authors attributed a novel negative role to TREM1 in cognitive decline in aging mice and in AD. Moreover, the effect of TREM1 on cognitive aging was found to be mediated predominantly by peripheral myeloid cells and not microglia.
Of note, TREM1 has been studied in cancer. Its expression is elevated in the tumor microenvironment, likely due to its expression by tumor-infiltrating myeloid cells. It is gratifying to see additional similarities between the cancer microenvironment and neurodegenerative disease.
The highly deleterious role of basal TREM1 signaling in aging, driven by its disruption of myeloid glucose and nucleotide metabolism, is consistent with the general notion that systemic immune dysfunction is a major contributing factor to age-associated cognitive decline and neurodegeneration. The present findings are in line with the notion that monocyte-derived macrophages are important players in defeating AD, and proposes that modifying circulating monocytes could provide a critical disease-modifying effect needed to slow or arrest progression to AD.
View all comments by Michal SchwartzMake a Comment
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