Aakancha Shaw, St. Xavier’s College, Kolkata
When we talk about the most common form of dementia Alzheimer’s Disease comes to our mind. This disease is characterized by the build-up of amyloid plaque in the brain. Microglia that are considered to be the immune Sentinels of the brain not only eliminate foreign invaders but are also responsible for maintaining brain homeostasis by clearing toxic waste build-up such as amyloid plaques. However, the role of microglia in Alzheimer’s Disease and clearing toxic waste and its role and relationship to amyloid plaque accumulation remains unclear. A team of scientists from Duke-NUS Medical School and MonashUniversity found that the gene expression signatures underlying microglia are known to be associated with amyloid plaque phagocytosis which is the engulfing of deposits of the amyloid-beta protein in the brain. The finding was reported in the journal Nature communication. The Journal offered a new target for interventions that aimed to address the underlying disease mechanism of the incurable disease named Alzheimer’s Disease. The team of scientists at Monash and Duke-NUS investigated to find out the difference between a healthy brain and the brains of patients with Alzheimer’s disease at the single-cell resolution. The scientists took a resolution to study gene expression changes in specific human brain cell types comprehensively that are associated with the progression of Alzheimer’s Disease. They were trying to understand the molecular mechanisms and the differences between and microglia that were engulfing amyloid plaques in Alzheimer’s disease and the ones that were not.
The team did this experiment by using a stain known as methoxy-XO4, which is specifically known to target microglia that have engulfed amyloid plaques. They made use of the stain in preclinical models of Alzheimer’s disease and then extensively examined gene expression in the stained microglia. After this, they investigated differences in gene expression underlying microglia’s ability to amyloid plaque and identified associated regulatory molecules. The was important to understand that mechanism because there were several new targets to go after and in the future the targets night open up a new front against this devastating disease. The studies and experiments revealed that microglia that had not taken up the amyloid plaques had their gene expression patterns almost similar to aged microglia which are known to be dysfunctional and is a major factor in Alzheimer’s disease pathogenesis. Also, after the microglia engulfed the amyloid plaques associated with the disease they seemed to develop a characteristic expression pattern, this change in gene expression is induced by a gene called hif1a. The changed gene expression was known to increase the ability of microglia to take up proteins such as amyloid while reducing hif1a decreases the ability of microglia to take up such proteins. Hence, the regulatory role of hf1a might also apply to the microglia function of eliminating damaged synapses. Hence, this process may be initially protective with the microglia effectively pruning damaged synapses that are located near the plaques. The relationship between Hif1a and cognitive decline in Alzheimer’s disease is yet to be comprehensively studied to uncover a lot of facts.
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Source: Grubman, A., Choo, X.Y., Chew, G. et al. Transcriptional signature in microglia associated with Aβ plaque phagocytosis. Nat Commun 12, 3015 (2021). https://doi.org/10.1038/s41467-021-23111-1
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