Distinct Signatures for Human Microglia in Alzheimer's Disease

Researchers are increasingly focusing on the role of the central nervous system innate immune cells known as microglia in the development of neurodegenerative disease. Primarily, this is thought to be a matter of immune cells entering a more inflammatory state, whether that is driven by cellular senescence, activation by damage-associated molecular patterns such as mislocalized mitochondrial DNA, or reaction to persistent infection. Clearing at least some of these inflammatory microglia, such as via the use of senolytic drugs that can pass the blood-brain barrier to force senescent microglia into programmed cell death, has been shown to reduce markers of pathology in mouse models of Alzheimer's disease. The same is true of methods that clear all microglia.

In today's open access paper, researchers classify transcriptomic patterns of microglial state to suggest that it isn't just inflammatory cells, but there are also other forms of dysfunction in microglia that are distinct to the Alzheimer's brain. This is intriguing, but note that the data doesn't tell us whether any specific grouping of immune cell behaviors associated with Alzheimer's is relevant to the creation of the disease state, versus being a side-effect of the disease state, or even the degree to which it contributes to pathology, if it does contribute. This is ever the challenge in age-related diseases; there are many identifiable changes in biochemistry, and considerable difficulty in determining which are important.

Human microglia show unique transcriptional changes in Alzheimer's disease

Microglia, the innate immune cells of the brain, influence Alzheimer's disease (AD) progression and are potential therapeutic targets. However, microglia exhibit diverse functions, the regulation of which is not fully understood, complicating therapeutics development. To better define the transcriptomic phenotypes and gene regulatory networks associated with AD, we enriched for microglia nuclei from 12 AD and 10 control human dorsolateral prefrontal cortices (7 males and 15 females, all 60 years or older) before single-nucleus RNA sequencing. Here we describe both established and previously unrecognized microglial molecular phenotypes, the inferred gene networks driving observed transcriptomic change, and apply trajectory analysis to reveal the putative relationships between microglial phenotypes.

This study identified 10 distinct microglia clusters from aged human brain. These included previously described homeostatic, senescent, and inflammatory microglia transcriptional phenotypes as well as additional clusters of transcriptional specification, which may give insight into AD pathogenesis, providing a platform for hypothesis generation. We describe the diversity of microglia clusters with endolysosomal gene signatures, one of which is enriched with nucleic acid recognition and interferon regulation genes. Inferred gene networks predict that individual clusters are driven by distinct transcription factors, lending further support for the functional diversity of clusters. Using trajectory inference analysis, we observed transitions in microglia phenotypes and predicted relationships that can be tested experimentally. AD cases were distinguished by the emergence of a subcluster expressing homeostatic genes that was characterized by altered transcription of genes involved in calcium activation, response to injury, and motility pathways.

Among the nuclei meeting criteria for a microglia transcriptomic signature, an 'aging signature' was observed in all clusters in this study, consistent with our older age cohort. Inflammaging may not only confound interpretations of gene expression profiles attributable to AD but may also contribute to the disease mechanisms hypothesized to drive AD. Additional studies exploring differences between younger controls and early-onset AD may also help to explore the aging, inflammaging, and AD-specific signatures.