A new study shows that microglia, which are the immune cells of the central nervous system, can “remember” inflammation. This “memory” influences how the cells react to new stimuli and deal with toxic plaque in the brain, a marker of Alzheimer’s disease.

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The brain’s immune cells remember previous inflammation.

Microglia, sometimes referred to as “scavenger” cells, “are the primary immune cells of the central nervous system.”

As the key player in the brain’s immunity, microglia are dispatched to the site of infection or injury, where they fight toxic agents or pathogens and get rid of useless cells.

However, these cells are also known to play a negative role in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, ischemic stroke, and traumatic brain injuries.

For instance, a recent study showed that when microglia are overactive, they devour toxic plaques along with synapses, which presumably leads to the neurodegeneration seen in Alzheimer’s.

Additionally, microglia survive for a very long time, with some of the cells lasting for over 2 decades.

Also, “[s]tudies have shown that infectious diseases and inflammation suffered during a lifetime can affect the severity of Alzheimer’s disease much later in life,” explains lead investigator Jonas Neher, an experimental neuroimmunology researcher at the German Center for Neurodegenerative Diseases in Tübingen.

Together, these observations led Neher to wonder “whether an immunological memory in these long-lived microglia could be communicating this [Alzheimer’s] risk.”

To answer this question, the team examined the immune response of these brain cells in mice. The findings were published in the journal Nature.

Neher and colleagues caused inflammation in mice several times and studied the effect that it had on their microglia. The researchers triggered two distinct states in the brain’s scavenger cells: “training” and “tolerance.”

For instance, the first inflammatory stimulus that the researchers applied “trained” the immune cells to react more strongly to the second inflammatory stimulus. But, by the fourth stimulus, the cells had become tolerant to inflammation and barely reacted at all.

Thus, it became evident that microglia can “remember” a previous inflammation.

The scientists then wanted to know what role this memory plays in how the microglia respond to the buildup of amyloid plaque in the brain, which is a hallmark of Alzheimer’s disease. So, they examined the activity of microglia in mice that had Alzheimer’s-like pathology.

Neher and team found that trained immune cells exacerbated the disease in the long-term. Months after their first inflammatory stimulus, microglia boosted the production of toxic plaques. Tolerant microglia, on the other hand, reduced plaque formation.

“Our results identify immune memory in the brain as an important modifier of neuropathology,” explain the researchers.

Furthermore, the researchers wanted to know if this immune memory left an epigenetic trace — that is, if the memory of inflammation would cause chemical changes to the cells’ DNA.

DNA analyses revealed that months after the first inflammatory stimulus, both “trained” cells and “tolerant” ones had epigenetic changes that activated some genes and switched off others.

Such epigenetic changes influenced the microglia’s ability to clear out toxic plaques in the brain.

“It is possible that also in humans, inflammatory diseases that primarily develop outside the brain could trigger epigenetic reprogramming inside the brain,” speculates Neher.

If this is true, it would explain why inflammatory illnesses such as arthritis — and diseases that have been proposed to be inflammatory, such as diabetesraise the risk of Alzheimer’s disease.

Next, the researchers plan to study whether microglia are altered in the same way in humans. If they are, this could open the door to innovative therapies.