New paper investigates microglial ultrastructure and interactions in Alzheimer’s disease

One of the many challenging and currently incurable illnesses the aging members of our society face is Alzheimer’s disease, a neurodegenerative disorder that severely impacts a patient’s quality of life. Researchers are trying understand the complex mechanisms involved in this disease in the hope of finding one day novel therapeutic avenues. One of the pieces at the centre of this puzzle is microglia, the resident immune cell of the brain.

Marie-Kim St. PierrePhD student Marie-Kim St-Pierre (pictured; Tremblay Lab) contributed to this ongoing work with her new first-author article, published in the Journal of Neuroinflammation, on microglial ultrastructure and how microglia interact with other brain elements and pathological hallmarks in Alzheimer’s disease. Fellow PhD students Micaël Carrier, Fernando González Ibáñez, and Eva Šimončičová (all, Tremblay Lab) also contributed to the article.

Marie-Kim and the team used electron microscopy to investigate dark microglia, a form of microglia associated with cellular stress and that interacts extensively with synapses. “What is really interesting about these cells is that they only appear in high numbers in pathological conditions” says Marie-Kim. “We knew that they were often seen in Alzheimer’s disease, but we hadn’t yet compared their cellular content to non-dark microglia, which would provide us more information on their role in the disease.”

Marie-Kim and the team found that dark microglia have a high rate of interaction with dystrophic neurites – impaired neuronal elements – that are often found accumulated near amyloid beta plaques. These plaques are one of the pathological signs of Alzheimer’s disease and are thought to underlie the progressive impairment of learning and memory associated with this condition.

Their study also showed for the first time ultrastructural evidence of glycogen granules – a form of glucose storage – in microglia. The team predominately observed them in dark microglia found near amyloid plaques. (There was also some evidence of the granules in non-dark microglia in the same areas.) The granules, along with the high presence of structurally altered organelles in the immune cells, may indicate a shift in the microglia’s metabolism.

“We now know that our metabolism is extremely affected by the pathogenesis of Alzheimer’s disease, and this study further confirms the disorder’s impact on microglia metabolism,” says Marie-Kim.

The fact that the team, in collaboration with Dr. Martin Parent from the CHU Research Centre of Québec-Université Laval, found dark microglia in post-mortem human brain samples during this study is also significant. “This was a defining moment since it means that what we study in non-human brains is relevant to the human condition,” says Dr. Marie-Ève Tremblay.

Using the knowledge generated on the specific ultrastructural signature of dark microglia observed in this study, the Tremblay Lab plans to test therapeutic strategies that would modulate microglia metabolism, with the aim of normalizing the function of these cells along the aging trajectory.

Marie-Kim intends to further investigate altered microglial metabolism in the context of brain cancer during her post-doctoral fellowship.