An immunological memory in the brain

April 11, 2018, German Center for Neurodegenerative Diseases
Credit: CC0 Public Domain

Inflammatory reactions can change the brain's immune cells in the long term—meaning that these cells have an "immunological memory." This memory may influence the progression of neurological disorders that occur later in life, and is therefore a previously unknown factor that could influence the severity of these diseases. Scientists at the German Center for Neurodegenerative Diseases (DZNE), the Hertie Institute for Clinical Brain Research (HIH), and the University of Tuebingen report on this in the journal Nature. Their study is the result of a collaborative effort also involving researchers from Goettingen, Bonn, and Freiburg.

Microglia are immune cells that only occur in the brain. They protect the brain by cleansing it of intruders and toxic substances. However, in certain situations they can also cause damage. Therefore, they have long been suspected of playing a central role in .

As are very long-lived, the scientists were keen to find out whether environmental factors change these over time and what effect this can have on brain health. "Epidemiological studies have shown that infectious diseases and inflammation suffered during a lifetime can affect the severity of Alzheimer's much later in life. We therefore asked ourselves whether an in these long-lived microglia could be communicating this risk," explains Dr. Jonas Neher, head of the current study and a scientist at the DZNE and the HIH.

Stimulated immune reaction

In order to address this question, Neher and colleagues triggered inflammation in mice, outside their brains; it was already known that such an inflammation can stimulate an in the brain. However, it was not clear whether microglia might be able to remember a previous inflammation. As it turned out: Depending on how often the scientists repeated this process, they were able to induce two different states in the microglia: "training" and "tolerance." The first inflammatory stimulus trained the microglia, causing them to react more strongly to the second. However, after a fourth stimulus, tolerance had occurred and the microglia barely responded.

Next, the researchers investigated how microglia training and tolerance affected the formation of in the long term. Such "plaques" are characteristic toxic deposits that accumulate in the brains of patients with Alzheimer's disease. In a mouse model of Alzheimer's pathology, the scientists observed that trained microglia amplified the formation of plaques even months after their immunological memory had been triggered, thus causing the disease to become more severe. In contrast, tolerant microglia reduced plaque load. The scientists also noticed similar effects in a mouse model of stroke.

Changes in DNA

In order to understand these effects more precisely, Neher and coworkers investigated in the microglia, i.e. chemical modifications to the DNA or its packaging proteins that cause certain genes to become more or less active. As epigenetic modifications are very stable, the researchers saw in them a possible cause for the long-term behavioral changes exhibited by the microglia. This hypothesis turned out to be correct: even many months after the initial immune stimulus, both the trained and the tolerant microglia showed specific epigenetic changes and corresponding differences in gene activation. This molecular reprogramming changed important functions in the microglia, such as their ability to remove amyloid plaques. And this affected Alzheimer's pathology.

Consequences for neurodegenerative diseases?

"It is possible that also in humans, inflammatory diseases that primarily develop outside the brain could trigger epigenetic reprogramming inside the brain," says Neher. Both infections and diseases such as diabetes or arthritis are associated with inflammatory reactions and are known risk factors for Alzheimer's disease. The 's immunological memory—epigenetically modified microglia—is one possible explanation for this effect. Therefore, Neher and colleagues are now investigating the conditions under which microglia undergo epigenetic changes in humans and looking at the therapeutic possibilities that may arise from this.

Explore further: Rejuvenating the brain's disposal system

More information: Wendeln, Degenhardt et al. (2018): "Innate immune memory in the brain shapes neurological disease hallmarks", Nature; DOI: 10.1038/s41586-018-0023-4

Related Stories

Rejuvenating the brain's disposal system

December 21, 2016
A characteristic feature of Alzheimer's disease is the presence of so called amyloid plaques in the patient's brain - aggregates of misfolded proteins that clump together and damage nerve cells. Although the body has mechanisms ...

Brain defense cells live longer than expected

August 29, 2017
Eliminating pathogens and cellular waste is an important task of microglia, the immune cells of the brain. They are among the group of non-neural brain cells that support the normal function of nerve cells. A new study now ...

Immune cells may protect against Alzheimer's

May 19, 2016
Clusters of immune cells in the brain previously associated with Alzheimer's actually protect against the disease by containing the spread of damaging amyloid plaques, a new Yale University School of Medicine study shows.

Overactive scavenger cells may cause neurodegeneration in Alzheimer's

June 30, 2017
For the first time, researchers from the University of Zurich demonstrate a surprising effect of microglia, the scavenger cells of the brain: If these cells lack the TDP-43 protein, they not only remove Alzheimer's plaques, ...

Chinese scientists decipher origins of repopulated microglia in brain and retina

March 1, 2018
The regenerative capability of the central nervous system (CNS) is largely limited due to its intrinsic properties and external environment. Traditional thinking holds that once the brain is injured, it is impossible to repair ...

Caloric restriction in combination with low-fat diet helps protect aging mouse brains

March 12, 2018
A low-fat diet in combination with limited caloric consumption prevents activation of the brain's immune cells—called microglia—in aging mice, shows research published today in Frontiers in Molecular Neuroscience. The ...

Recommended for you

Scientists unearth vital link between fat, immunity and heat regulation

April 24, 2018
Scientists have just made a surprising discovery involving fat and special immune cells that live within it—it turns out that 'gd T cells' are the key cogs in the biological wheel that regulates our body heat and protects ...

Brain activity linked to stress changes chemical codes

April 24, 2018
Five years ago, a team of University of California San Diego neurobiologists published surprising findings describing how rats' brain cells adopted new chemical codes when subjected to significant changes in natural light ...

Immune response might be stunting growth in millions of kids

April 24, 2018
An overactive immune system during childhood among young people in Ecuador's indigenous Shuar population comes with a cost: stunted growth.

Scientists develop new method that uses light to manage neuropathic pain in mice

April 24, 2018
For patients with neuropathic pain, a chronic condition affecting 7 to 8 percent of the European population, extreme pain and sensitivity are a daily reality. There is currently no effective treatment. Scientists from EMBL ...

Animal cyborg—behavioral control by activating 'toy craving' circuit

April 24, 2018
Children love to get toys from parents as presents. This craving for objects also underlies object hoarding disorders and shopping addiction. However, the biological causes of object pursuit have remained unknown. Part of ...

Imagined and actual movements are controlled by the brain in the same way

April 24, 2018
A new study from Karolinska Institutet in Sweden shows that imagined movements can change our perception in the same way as real, executed movements do. The research, which is presented in the scientific journal Nature Communications, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.