"We discovered the transcription factor Hif1a to be at the center of a regulatory network that controls the phagocytosis capacity of the microglia in AD," Dr. Jose Polo of Monash University in Victoria and Dr. Enrico Petretto of Duke-National University of Singapore Medical School told Reuters Health by email.
"This relationship between the activity of Hif1a...and the extent of cognitive decline in AD patients is yet to be fully elucidated," they said. "Large-scale studies in AD patients with varying degrees of cognitive decline will be important."
As reported in Nature Communications, building on previous work in which they generated a single-cell atlas of the brain from individuals with AD (https://go.nature.com/3pfsN4W), the team analyzed amyloid plaque-containing and non-containing microglia from an AD mouse model.
Transcriptomics analysis identified different transcriptional trajectories in aging and AD mice. Plaque-containing microglial transcriptomes exhibited dysregulated expression of genes associated with late-onset AD.
By contrast, non-plaque-eating microglia had transcriptional signatures associated with accelerated aging, and contained more intracellular postsynaptic material than plaque-eating microglia, even though phagocytosis was reduced.
Additional investigations showed that the transcriptional program associated with plaque-containing microglia from mice is also present in a subset of human microglia isolated from the brains of individuals with AD.
As Drs. Polo and Petretto noted, HIF1a was identified as potentially regulating synaptosome phagocytosis in in vitro studies of human microglia and mouse model microglial cells.
Further, computational modeling predicted the networks of molecules involved in microglia uptake of proteins such as amyloid, and identified potential candidate drugs. For example, rapamycin was shown to block Hif1a from triggering microglia to engulf amyloid plaques, which could be important if phagocytosis goes awry.
Drs. Polo and Petretto added, "It is intriguing to hypothesize that the activity of Hif1a in microglia might well play an important role in other brain disorders such as Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, and diseases characterized by cognitive impairment."
"With the growing number of large-scale single-cell level studies of different brain diseases, we believe that more evidence will come to light to corroborate or disprove this hypothesis," they conclude.
Dr. Rebecca Edelmayer, the US Alzheimer's Association's Senior Director of Scientific Engagement, commented in an email to Reuters Health, "Many researchers are working on therapeutics that target microglia; there are already clinical trials ongoing."
Nonetheless, she said, "Microglia can be difficult to study, particularly when you are trying to mimic their typical human functions in cellular and animal models. Their role, functionality and effectiveness can change over time, depending on a multitude of factors."
"This study tries to shed light on therapeutic targets that may impact the balance of necessary/essential microglia activity with abnormal/dysfunctional activity," she said. "In order to discover effective treatments, we may need the right balance of microglia 'clean up' activities going on in the brain."
"Too little microglial activity may lead to abnormal amyloid build up," she noted, "and too much or abnormal microglial activity may lead to destruction of potentially salvageable synapses that may be sick, but not beyond repair."
"It's important that we study not only what is going wrong in the brain of individuals with Alzheimer's, but also what is going right to develop targeted approaches," she added.
She noted that one Alzheimer's Association-funded study is testing rapamycin, which was also used in the current study, to modulate the microglia function and prevent the dysfunctional destruction of brain synapses. (https://bit.ly/3uLampN)
SOURCE: https://go.nature.com/34FKRvt Nature Communications, online May 21, 2021.
By Marilynn Larkin
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