A New Target for Intervention in Alzheimer Disease?

Paul Gleason, PhD

Gene expressions in microglia cells may explain why some of them are ineffective and allow dementia to progress.

A recent study published in Nature Communications has partially clarified the role of microglia cells in the progression of Alzheimer disease (AD), which in turn may lead to new targets for intervention.1

Normally, microglia cells are responsible for clearing out amyloid plaques and other kinds of cellular debris, but in cases of AD progression they generally do not.1,2 Investigators at Duke-National University of Singapore (NUS) Medical School and Monash University set out to discover why. “We sought to understand the molecular mechanisms and differences between microglia that were actively engulfing amyloid plaques in Alzheimer’s disease and those that weren’t,” Enrico Petretto, PhD, associate professor at Duke-NUS Medical School, said in a statement to the press.2

When comparing microglia that were and were not eliminating amyloid plaque, Petretto and his co-investigators found that they had different gene expression patterns induced by the Hif1a gene. The researchers found that microglia cells with reduced Hif1a expression also had a decreased ability to take up and eliminate an abnormal protein like amyloid. Conversely, high expressions of Hif1a were associated with more active and effective microglia cells.2

“Understanding this mechanism is important because now we have several new targets to go after, and in the future, these targets may open a new front against this devastating disease,” added Jose M. Polo, PhD, an ARC Future Fellow at Monash University.2 This research is built on a larger Duke-NUS initiative to create a comprehensive map of gene expression changes that are associated with AD progression.3

Since the exact relationship between Hif1a and AD remains incompletely understood, “future work could focus on using gene editing tool CRISPR to test the impact of manipulating Hif1a on symptom severity and disease progression,” Gabriel Chow, MD-PhD candidate at Duke-NUS Medical School, further explained.2

References

1. Grubman A, Choo XY, Chew G, et al. Transcriptional signature in microglia associated with Aβ plaque phagocytosis. Nat Commun. 2021;12(1):3015.

2. Scientists discover gene signature for plaque-eating microglia in Alzheimer’s disease. FirstWord Pharma. May 23, 2021. Accessed May 27, 2021.

3. Duke-NUS study reveals how individual cell types in the brain contribute to Alzheimer’s disease. Duke-NUS Medical School. November 28, 2019. Accessed May 27, 2021.