Healthcare (Commonwealth Union) – A recent preclinical study by Weill Cornell Medicine researchers reveals that microglia, immune cells in the brain, can partially break down large amyloid plaques associated with Alzheimer’s disease. These cells latch onto the plaques, forming an external “stomach” and releasing digestive enzymes to break them down. The findings, published on December 6 in Cell Reports, could pave the way for therapies aimed at enhancing microglia’s ability to clear amyloid plaques.
The process, known as digestive exophagy, may also shed light on why microglia have been reported to both degrade and, paradoxically, spread amyloid plaques in Alzheimer’s disease.
Microglia, the brain’s scavengers, are responsible for cleaning up cellular debris, microbes, and dead cells. They do so by surrounding and encapsulating these materials in vesicles, which transport the cargo to lysosomes—membrane-bound organelles filled with digestive enzymes. While researchers suspected that microglia could break down amyloid plaques, the challenge was understanding how these cells could tackle such large aggregates, far bigger than themselves.
“We found that the cells basically attach a lysosome onto a large plaque, and they expel enzymes into the space that can digest the amyloid,” explained Frederick Maxfield, M.S. ’73, Ph.D. ’77, the Vladimir Horowitz and Wanda Toscanini Horowitz Distinguished Professor in Neuroscience at Weill Cornell Medicine.
Maxfield was reminded of macrophages, immune cells that perform a similar scavenging function throughout the body, when considering how microglia might consume something large in the brain. In past research, his lab discovered that when macrophages encounter an object too big to engulf—like a mass of lipoproteins in an atherosclerotic plaque—they create an external digestive compartment that breaks down the mass bit by bit using lysosomal enzymes.
To explore whether microglia follow a similar process, the research team, led by Santiago Solé-Domènech, assistant professor of research in biochemistry, and Rudy Jacquet, a doctoral student at Weill Cornell Graduate School of Medical Sciences at the time, began by examining cultured mouse microglial cells.
Through a series of experiments, they demonstrated that when a microglial cell came into contact with a large amyloid plaque in a petri dish, it formed a partially enclosed space around the plaque, much like macrophages do. “The microglial lysosomes released their contents and acidified the area to activate the enzymes responsible for digesting the amyloid deposits,” Maxfield explained.
The team then turned to a mouse model of Alzheimer’s disease. Co-author Marie-Ève Tremblay, a professor at the University of Victoria, used electron microscopy to examine brain samples and identified pockets formed by microglial cells around plaques, characteristic of a digestive process called exophagy. She also detected the presence of a lysosomal enzyme within the space.
Microglia play a role in both breaking down plaques and contributing to their formation, which presents a paradox that intrigued the researchers. They speculated that digestive exophagy might be involved in transferring Alzheimer’s plaques to other regions of the brain.
In earlier studies, the team introduced smaller plaque fragments, known as amyloid fibrils, into cultured microglial cells. The cells took an extended period to break down these fragments in their internal lysosomes, eventually releasing the indigestible remnants.
In their latest experiment, the researchers loaded the microglia with amyloid fibrils but positioned them near larger plaques. Sole-Domenech indicated that they observed that while the microglia attempted to engulf the plaques, they were already burdened with amyloid fibrils, which caused them to release these smaller fragments towards the plaques.
Researchers of the study indicated that microglia cells have the ability to move in a speedy manner throughout the brain, so they are able to easily move to a different location once a plaque is digested. Maxfield pointed out that, if microglial cells begin to do digestive exophagy on another large object, they could release those seeds of amyloid fibrils into a new area.
