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Microglial Epigenetics Hints at How ApoE Toggles Alzheimer’s Risk

Series - Alzheimer's Association International Conference (AAIC) 2024:

At the AAIC conference held 27 July to 1 August in Philadelphia, microglial epigenetics stood in the limelight. Microglia are infamous for their dynamic and varied responses to different threats they encounter within the brain environs, and epigenetic approaches hold promise for learning what controls these shifty cells.

  • When faced with amyloid, transplanted human microglia respond differently based on their ApoE genotype.
  • E4 microglia crank up pro-inflammatory genes, downregulate many AD genes.
  • ApoE2 microglia facilitate protective responses, by way of Vitamin D receptor.

At AAIC, scientists reported that the “landscape” of exposed enhancer sequences helps them infer master transcription factors in charge of orchestrating responses to amyloid and to signaling via the TREM2 receptor (see prior story). Other groups used xenotransplant models to decipher epigenetic responses of human microglia to amyloid in their mouse hosts. They discovered stark differences by ApoE genotype, whereby ApoE4 microglia mounted largely pro-inflammatory responses to amyloid, with many of their dysregulated genes overlapping with AD risk genes. ApoE2 microglia, on the other hand, stayed calm and collected, enhancing their signaling via the anti-inflammatory vitamin D receptor.

Sarah Marzi of King’s College London presented these findings. Drawing from a hefty epigenetic toolbox in her lab, Marzi is scouring the microglial genome for both chromatin accessibility and acetylation. She is looking to spot regions that show active versus repressed gene expression, and she corroborates those epigenetic measures with transcriptomics. For her current study, Marzi wanted to know how ApoE genotype influences the way microglia respond to amyloid. To that end, she teamed up with Bart de Strooper of KU Leuven and Renzo Mancuso of the University of Antwerp, who have developed xenotransplantation models to study human microglia respond to threats they encounter in the mouse brain (Oct 2022 news).

Many of the findings Marzi presented are now posted in a preprint (Murphy et al., 2024). 

When Di Hu and Kitty Murphy in Marzi’s lab applied their omics techniques to human microglia isolated from the amyloid-ridden brains of 1-year old-APP knock-in mice, they found widespread epigenetic and transcriptomic differences based on microglial ApoE genotype. One standout was CHCHD2. This gene encodes a mitochondrial protein involved in myriad functions, including cell motility and the response to hypoxia. In ApoE2 and ApoE3 microglia, CHCHD2 transcripts were abundant, and the gene’s promotor was exposed in open chromatin. The opposite was true in both ApoE knockout and ApoE4 microglia. In them, CHCHD2 transcripts were nonexistent, and chromatin around the gene’s promotor was closed up tight.

This same finding between ApoE4 and ApoE knockouts went beyond CHCHD2. In fact, Marzi saw considerable overlap in the epigenetic and gene expression changes mounted by both their microglia in response to amyloidosis. Notably, many genes with variants implicated in AD risk were among those turned down in both ApoE4 and ApoE knockout microglia. That ApoE4 spurred some similar gene expression changes as did ApoE knockout suggests that E4 exerts some of its influence on AD risk via a loss of protective function. This manifests in the downregulation of beneficial genes.

In Philadelphia, Marzi noted that the convergence between ApoE4 genotype and expression of other AD risk genes argues against the recently proposed idea that ApoE4 homozygosity is a distinct form of AD (May 2024 news). “What we see here at the transcriptional level would suggest that is not true, because the changes associated with ApoE4 are mimicked by the overall genome-wide heritability of AD,” Marzi said.

ApoE2 and ApoE4 microglia also mounted qualitatively different inflammatory responses to amyloid. Microglia expressing ApoE4 revved up a host of pro-inflammatory cytokines, including CCL4L2, CCL3, CCL3L1, whereas cells expressing ApoE2 ramped up CXCL16, which reportedly has an anti-inflammatory effect.

Soothing Sunshine? Epigenetics suggest a boost to the vitamin D receptor response in ApoE2 microglia, whereby activation of the nuclear VDR enhances expression of target genes including the IL-10 receptor, which quells pro-inflammatory signaling via SOCS3. [Courtesy of Sarah Marzi, King’s College London.] [Courtesy of Sarah Marzi, King’s College London.]

Another example in support of ApoE2’s anti-inflammatory prowess came from an enhancer motif analysis similar to those conducted by Christopher Glass, University of California, San Diego, and Katherine Monroe, Denali (see previous story). The London scientists hunted for differentially exposed enhancer sequences in open, hyper-acetylated stretches of chromatin within the isolated microglia. What was the top discriminator between ApoE2 and ApoE4 microglia? A DNA-binding motif that binds the vitamin D receptor, which is a ligand-inducible transcription factor that orchestrates responses to vitamin D. In particular, regions with greater chromatin accessibility in ApoE2 microglia were strongly enriched for this motif.

Did these exposed motifs translate into a stepped-up vitamin D response? Indeed, by referencing the transcriptomic data they collected from the same samples, the researchers found an uptick in expression of genes known to be upregulated by VDR signaling in ApoE2 microglia, but not in ApoE4 ones. One such gene was the alpha subunit of the IL-10 receptor, which mediates anti-inflammatory signaling. Together, the findings mesh with other data casting ApoE2 and ApoE4 as anti- and pro-inflammatory mediators, respectively. They also jibe with reported associations between vitamin D deficiency and AD, Marzi noted.

“Vitamin D acts via binding to VDR, and enrichment of VDR in regions with increased chromatin accessibility in APOE2 may therefore enable these microglia to be more responsive to vitamin D, regardless of serum levels,” the authors wrote in their preprint.—Jessica Shugart 

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References

News Citations

  1. I’m Open! Exposed Enhancers Reveal Masters of Microglial Moods
  2. Human Microglia Mount Multipronged Response to AD Pathology
  3. Do Two APOE4 Alleles Always Mean Alzheimer's?

Mutations Citations

  1. APOE C130R (ApoE4)
  2. APOE R176C (ApoE2)

Paper Citations

  1. Murphy KB, Hu D, Wolfs L, Mancuso R, DeStrooper B, Marzi SJ. The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer's disease. 2024 Jul 05 10.1101/2024.07.03.601874 (version 1) bioRxiv.

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