Marie-Ève Tremblay, her research team and partners at the City University of New York (CUNY) reported some first-in-world findings recently. While the others did the biological and biochemical procedures, the UVic professor and Canada Research Chair and her crew of Mohammadparsa Khakpour, Colby Sandberg, Fernando González Ibáñez and Olivia Braniff performed the electron microscopy experiments. Together, they were seeking the agents — secret until now — that cause the devastating damage of Alzheimer’s disease.
With a unique partnership and combination of technologies, their breakthrough illuminates a promising target for therapies that could slow and maybe even reverse the disease’s development.
Brain cells called microglia were discovered in 1918 by Spanish scientist Pío del Río Hortega. Almost a hundred years later, in 2010, Tremblay and other teams showed the world that they are active immune cells playing key roles, not only clearing away pathogens and toxic debris, but also remodelling synapses — the communication points between nerve cells.
Dark Microglia
Then, in 2016, she shared another global-first finding: a subset of microglia that aren’t such a force for good. Quite the opposite, in fact. Tremblay called them dark microglia because they’ve undergone molecular changes that render them darker — and therefore easier to see — under the electron microscope.
In contrast to typical microglia, these cells appear to destroy healthy synapses, and they are thought to open the blood-brain barrier, which exposes the brain to toxic and inflammatory agents. Both of these actions could lead to cognitive decline and the march of devastation across neurological conditions including depression, schizophrenia, cognitive aging, and Alzheimer’s disease.
What’s more, Tremblay showed that dark microglia aren’t abundant in healthy adult brains, illustrating that they are specifically associated with disease, increasing in number up to 10-fold during aging and pathology.
This most recent study, published in Neuron, took the research and the findings to a new level.
“The association with disease was known for years,” she says, “but not the consequences. That is, do dark microglia cause pathology?”
The answer, it turns out, is yes, they do.
We needed this collaboration with CUNY to use the tools to induce cellular stress in microglia and therefore induce dark microglia. This technique is so unique. It’s what made these findings possible. We can now control dark microglia and study the outcomes.”
—Marie-Ève Tremblay, UVic professor and Canada Research Chair
Therapeutic potential
In mouse models, the team found that inhibiting lipid synthesis or the activation of the integrated stress response (ISR) in microglia prevented not only the increased abundance of dark microglia but also synapse loss and the accumulation of proteins that damage the nerve cells.
This offers a promising pathway for therapeutic intervention, says Khakpour, a research associate in Tremblay’s lab. It was he who analyzed the mouse models using the Tremblay’s lab CFI-funded electron microscope and spotted the classic hallmarks of microglial cells altered by stress.
And then he and the rest of Tremblay’s team took the research a step further. Using its electron microscope, they examined post-mortem human samples from the CERVO Brain Research Centre in Québec. This was yet another turning point in the study of these brain cells.
“We were able for the first time ever,” Tremblay says, “to quantify dark microglia in human tissue.”
They weren’t abundant in the healthy brains they examined — only in those with Alzheimer’s disease.
When Khakpour did more work with mouse and human samples, the team could observe lipid pockets in the dark microglia and, combined with other findings, this indicates that dark microglia are releasing the lipids at neurons, damaging and potentially killing them.
“Now we think dark microglia could be a cause,” Khakpour says, “and they’re important for the pathology.”
“We could demonstrate that these cells are detrimental in Alzheimer’s pathology,” Tremblay says, “and therefore could represent a promising therapeutic target.”
Looking ahead
Their next steps moved the research that much further forward, into a future with tangible hope: they tested some interventions preventing the release of toxic lipids and saw that they did indeed stop the dark microglia’s damaging behaviour. But that’s not the finish line, as far as the Tremblay crew is concerned.
“Even the stage of the disease – how could that affect the dark microglia?” wonders Khakpour. “There might be genetic modifications that would turn on or turn off cells. We can also explore the effects of sex differences, life stage, brain region….”
“The advantage of using electron microscopy,” Tremblay adds, “is that we see all of the cells, not just the cells we’ve marked, as happens with fluorescence for example. This Neuron study paves the way to look at dark microglia in humans using other techniques such as positron emission tomography (PET) scans. We can develop the tracers to see the cells.
I’ve long dreamed of seeing dark microglia at work and once we can study the effects in the patients, this will change neurology, it will change psychiatry.”
—Marie-Ève Tremblay, UVic professor and Canada Research Chair
