A rare but potent genetic mutation that alters a protein in the brain’s immune cells, known as microglia, can give people as much as a three-fold greater risk of developing Alzheimer’s disease.
“This TREM2 R47H/+ mutation is a pretty important risk factor for Alzheimer’s disease,” said study lead author Jay Penney.
In the study in the journal GLIA, Tsai and Penney’s team shows that human microglia with the R47H/+ mutation in the TREM2 protein exhibit several deficits related to Alzheimer’s pathology. Mutant microglia are prone to inflammation yet are worse at responding to neuron injury and less able to clear harmful debris including the Alzheimer’s hallmark protein amyloid beta. And when the scientists transferred TREM2 mutant human microglia into the brains of mice, the mice suffered a significant decline in the number of synapses, or connections between their neurons, which can impair the circuits that enable brain functions such as memory.
Penney, Tsai and their co-authors focused their work on human microglia cell cultures. To do this they used a stem cell line derived from skin cells donated by a healthy 75-year-old woman.
The team then looked to see how harboring the mutation affected each cell line’s expression of its genes. The scientists measured more than 1,000 differences but an especially noticeable finding was that microglia with the mutation increased their expression of genes associated with inflammation and immune responses. Then, when they exposed microglia in culture to chemicals that simulate infection, the mutant microglia demonstrated a significantly more pronounced response than normal microglia, suggesting that the mutation makes microglia much more inflammation-prone.
In further experiments with the cells, the team exposed them to three kinds of the debris microglia typically clear away in the brain: myelin, synaptic proteins and amyloid beta. The mutant microglia cleared less than the healthy ones.
Another job of microglia is to respond when cells, such as neurons, are injured. Penney and Tsai’s team co-cultured microglia and neurons and then zapped the neurons with a laser. For the next 90 minutes after the injury the team tracked the movement of surrounding microglia. Compared to normal microglia, those with the mutation proved less likely to head toward the injured cell.
Finally, to test how the mutant microglia act in a living brain, the scientists transplanted mutant or healthy control microglia into mice in a memory-focused region of the brain called the hippocampus. The scientists then stained that region to highlight various proteins of interest. Having mutant or normal human microglia didn’t matter for some measures, but proteins associated with synapses were greatly reduced in mice where the mutated microglia were implanted.
By combining evidence from the gene expression measurements and the evidence from microglia function experiments, the researchers were able to formulate new ideas about what drives at least some of the microglial misbehavior.
“Our findings highlight multiple effects of the TREM2 R47H/+ mutation likely to underlie its association with Alzheimer’s disease risk and suggest new nodes that could be exploited for therapeutic intervention,” the authors conclude.
Jay Penney, William T. Ralvenius, Anjanet Loon, Oyku Cerit, Vishnu Dileep, Blerta Milo, Ping‐Chieh Pao, Hannah Woolf, Li‐Huei Tsai. iPSC‐derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss. Glia, 2023; DOI: 10.1002/glia.24485
Picower Institute at MIT. “How a mutation in microglia elevates Alzheimer’s risk.” ScienceDaily. ScienceDaily, 16 November 2023. <www.sciencedaily.com/releases/2023/11/231116141032.htm>.
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