Normal aging increases white matter microglial reaction and perivascular macrophages in the microcebe primate

Summary:

Small primate shows big promise? Grey mouse lemur exhibits various age-related changes in microglia

Graphical abstract found in the highlighted preprint, made available under a CC-BY 4.0 license

Why I Highlight this Work

This study is the first to examine HLA-DR expression across aging in the microcebe brain. This work is important because it contributes to our understanding of the mechanisms of aging in a non-human primate, and provides a good initial characterization of activated microglia that can be expanded upon. It is exciting that these results align with those found in other studies on microglia in the white matter in various primate species, including humans.

Introduction/Background

Microglia are the resident immune cells of the central nervous system and play an important role in maintaining brain homeostasis and in responding to disease. In humans, microglia can undergo changes in proliferation, morphology, and phenotype during aging, and especially so with Alzheimer’s disease [1]. However, age-related changes in microglia are still not yet fully understood, particularly in non-human primates, which are valuable model organisms due to their genetic and physiological similarities to humans. 

The grey mouse lemur (Microcebus murinus) is one of the smallest and fastest-reproducing non-human primates, and can display age-related cognitive decline as well as amyloid and tau neuropathology [2]. Given that the mouse lemur is prime candidate for studying aging and neurodegenerative disease, it is important to further characterize cellular changes in its brain with age. To better understand microglial changes specifically, the authors used immunolabelling to analyze density and morphological differences in microglia expressing HLA-DR, a marker of microglia reaction, in several brain regions of middle-aged and aged mouse lemurs.

Key Findings

HLA-DR+ Microglia Density Increases with Age in White Matter

HLA-DR staining was variable across lemurs (ranging from no to high staining) and overall lower in the cortical regions compared to white matter. HLA-DR+ microglia tended to be rod-shaped in cases with low expression, while HLA-DR+ microglia displayed amoeboid morphology in cases with high expression. In the white matter, the authors found that aged lemurs had significantly higher expression of HLA-DR, measured as percent area coverage, in the corpus callosum and optic chiasma compared to middle-aged animals. In the corpus callosum, HLA-DR+ cell density was also significantly increased in the aged group and was higher posteriorly compared to anterior brain sections. The authors also observed increased expression in aged lemurs in the cingulate and parietal cortex, as well the hippocampus. 

Perivascular HLA-DR+ Microglia Density is Increased in Aged Lemurs

The authors also looked specifically at perivascular HLA-DR+ microglia by counting cells inside or near blood vessels. Aged lemurs showed increased HLA-DR+ microglial density in the parietal cortex, entorhinal cortex, and hippocampus, while there was no difference in overall vascular density. However, although the authors had observed an increase in HLA-DR expression in the cingulate cortex, they did not detect an increase in perivascular microglia in this region. 

Absence of HLA-DR+ Microglia Around Plaques in Aged Lemur with Amyloidosis

One aged lemur was excluded from the cohort due to the presence of amyloidosis, and evaluated as a case study instead. Surprisingly, the authors detected no HLA-DR+ microglia close to the diffuse amyloid plaques. 

Questions and Future Directions

1. As you mention, it would be interesting to investigate the correlation of microglial activation and cognition in the microcebe. Given what has been found in humans and macaques, what kinds of cognitive impairments would you expect to see correlated with presence of increased reactive microglia?
2. In your study, you had performed magnetic resonance imaging to verify that there was no obvious cerebral pathology in the animals. Did you observe white matter lesions on MRI in animals that had increased HLA-DR+ microglia densities?
3. I would be interested to see findings with more middle-aged animals included, or ages that fall in between the two groups in this study. In addition to that, were you able to look at age as a continuous variable?
4. Were you able to quantify the myelin-associated microglia you observed in the cingulate cortex?
5. I am interested in the spatial analysis of neuronal and glial changes around pathology in my own research. In your methods, how did you decide on the radius for determining perivascular microglia and plaque-associated microglia?

References 

1. Edler, M. K., Mhatre-Winters, I., & Richardson, J. R. (2021). Microglia in aging and Alzheimer’s disease: A comparative species review. Cells, 10(5). Artn 1138. https://doi.org/10.3390/Cells10051138 
2. Picq, J. L., Aujard, F., Volk, A., & Dhenain, M. (2012). Age-related cerebral atrophy in nonhuman primates predicts cognitive impairments. Neurobiology of Aging, 33(6), 1096–1109. https://doi.org/10.1016/j.neurobiolaging.2010.09.009

 

doi: https://doi.org/10.1242/prelights.41774

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