Immune Signalling Molecule Helps Prevent Alzheimer’s Disease Symptoms

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investigators discover a rare genetic variant shown to protect people who carry known genetic risk factors for Alzheimer's disease

An immune signalling molecule called interleukin (IL)-3, released by brain cells called astrocytes, programs other neuronal cells called microglia to start clearing the amyloid beta deposits and tau tangles seen in the brains of people with Alzheimer’s, according to research led by scientists at Massachusetts General Hospital.

Microglial cells are the brain’s main form of immune defense and act in a similar way to peripheral macrophages. They actually cause much of the damage seen in the brains of Alzheimer’s patients, as the amyloid and tau deposits trigger off an excessive immune response that causes over 10 times more damage than the deposits alone. Some people have been found to have amyloid and tau deposits, but no inflammation, and have little to no symptoms of Alzheimer’s disease.

But, as described in the Nature paper about the research, the IL-3 released by some astrocytes seems to turn the microglial cells back from being aggressive killers to more helpful cells that actually clean up the disease damage rather than making it worse.

“Once neurons start dying in increasing amounts, brain cells called microglia and astrocytes–which are normally nurturing cells that clean up debris–become activated to cause neuroinflammation in an attempt to protect the brain. They are evolutionarily programmed to wipe out a brain region where there is excess neuronal cell death because it may be due to an infection, which must be stopped from spreading,” explains co-senior author Rudolph Tanzi, co-director of the McCance Center for Brain Health at Massachusetts General.

Microglial cells were known to act in a range of different ways in people with Alzheimer’s but the exact mechanisms behind these differences were previously unclear. To investigate this further, Tanzi and colleagues created a mouse model of Alzheimer’s disease where the mice expressed different mutations. They found that mice that lacked IL-3 had greater numbers of amyloid plaques and worse disease symptoms than those with functional IL-3.

In order to find out where the IL-3 was coming from, the researchers used fluorescent labeling in a different mouse model to see which cells produced the immune protein. They found that a subset of astrocyte cells in the brain seem to produce IL-3. They also discovered that microglial cells are the target for IL-3 as they carry the IL-3Rα receptor.

The team also assessed if IL-3 and IL-3Rα played the same role in the human brain by comparing data and samples from people with Alzheimer’s disease and healthy controls and confirmed the same findings as in the mouse models.

Notably, the researchers found that injecting IL-3 into the brains of the mice with Alzheimer’s had a significant beneficial effect, reducing amyloid build up by triggering the microglia to switch to a clean up role, suggesting there may be a therapeutic angle to this finding.

“There may be important clinical implications to knowing that astrocytes talk to microglia via IL-3 to educate the microglia and help them decrease the severity of Alzheimer’s disease,” said Filip Swirski, co-senior author on the paper who was a principal investigator in the Center for Systems Biology at Massachusetts General while working on the study.

“We can now think about how to use IL-3 to not only help curb the neuroinflammation that carries out the bulk of neuronal cell death in Alzheimer’s disease, but also to entice microglia to once again take on the beneficial task of clearing away the deposits and tangles that are the initiating pathology of Alzheimer’s disease.”

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