Highly responsive immune cells seem to be beneficial for the brain
New insights into the mechanisms of neurodegenerative diseases

Date:
February 14, 2022
Source:
DZNE - German Center for Neurodegenerative Diseases
Summary:
New findings support the view that hyperactive immune cells
in the brain can have a protective effect in the course of
neurodegenerative diseases.



FULL STORY ========================================================================== Findings by researchers from Germany support the view that hyperactive
immune cells in the brain can have a protective effect in the course
of neurodegenerative diseases. Experts from Deutsches Zentrum fu"r Neurodegenerative Erkrankungen (DZNE), Ludwig-Maximilians-Universita"t
Mu"nchen (LMU) and LMU Klinikum Mu"nchen report on this in the scientific magazine The EMBO Journal. The scientists are currently considering that modulating the activity of immune cells in the brain via a receptor called TREM2 may significantly impact neurodegenerative disease processes. Thus,
they see activating TREM2 as a promising approach for drug research.


==========================================================================
The immune cells of the brain -- called "microglia" -- act against
pathogens, help to clear up cellular debris and also maintain neuronal
health. However, in Alzheimer's disease and other neurodegenerative
diseases, these cells enter a "hyperactive" state, traditionally
considered an excessive immune response because it is associated with
chronic and thus harmful inflammatory processes.

However, the current results put this view partly into a new perspective.

"Contrary to common belief, our findings support the hypothesis that hyperactive microglia have their good side. Recently, there has already
been some evidence for this. Our study now provides further indications,"
says Christian Haass, a research group leader at DZNE and professor of biochemistry at LMU Mu"nchen.

Antibodies in Action In previous studies, Haass and colleagues had
identified a protein called TREM2, which is anchored in the cell
membrane of microglia, as an "activity switch." Using antibodies that
bind and activate TREM2 -- co-developed with the U.S. company Denali Therapeutics -- the researchers succeeded in toggling this molecular
switch, thereby boosting microglial activity. "At the time, we saw
in laboratory experiments that microglia activated in this way more
effectively eliminate the protein deposits typical of Alzheimer's
disease, the notorious amyloid plaques," explains Haass. "However,
we were concerned that too much activation of microglia could cause
harm, as is commonly believed." The current studies expand upon the investigations carried out back then.

Instead of increasing microglia activity, the researchers now pursued
the opposite. "We wanted to know the impact on disease pathology when we downregulated the activity of hyperactive microglia," Haass says. This
time, an antibody was used that disabled the TREM2 receptor and thus
reduced the activity of the immune cells in the brain.

Laboratory Studies As an example of a neurodegenerative disease,
the researchers focused on "GRN- associated frontotemporal lobar
degeneration," GRN-FTLD for short. "This is a genetic, rare form of
dementia that comes with a wide range of abnormal behaviors. Some of
the affected individuals are impulsive and aggressive, while others
are apathetic," explains Prof. Dominik Paquet, a neurobiologist at the Institute for Stroke and Dementia Research at LMU Klinikum Mu"nchen,
whose research group was also involved in the current study.

"GRN-FTLD is well-described and there are good options for laboratory
studies.

Therefore, we used this disease as an example to investigate how
hyperactive microglia contribute to the pathology of neurodegeneration,"
says Dr. Anja Capell, biochemist at LMU Mu"nchen, who co-designed the
current study.

The research team used different cell cultures for their
experiments. These included either microglia derived from human stem
cells or cells obtained directly from patients with GRN-FTLD. Mice with
genetic traits characteristic of GRN-FTLD were also studied.

Less Microglial Activity Didn't Make It Better "Our data suggest that it
is indeed possible to diminish microglia activation state via inhibition
of TREM2 signaling. Hyperactivity is therefore reversible and not a
one-way street, which is not a given," says Anja Capell. "However,
the pathology was not improved but worsened as a result; loss of
contacts between neurons, the synapses, increased. We also found that
the level of a biomarker for neuronal damage rose." These results
are unexpected. "We were surprised ourselves. But contrary to common
belief, hyperactivated microglia seem to retain certain neuroprotective functions. At least this applies to the model system we studied," says Christian Haass. "Conversely, this means that a controlled increase in
the activity of microglia could help to contain the disease process to
some extent.

For this, I consider targeting the TREM2 receptor with an agonist
antibody, that's an activating antibody, to be promising. We
intend to pursue this idea further." special promotion
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Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Anika Reifschneider, Sophie Robinson, Bettina van Lengerich,
Johannes
Gno"rich, Todd Logan, Steffanie Heindl, Miriam A Vogt, Endy
Weidinger, Lina Riedl, Karin Wind, Artem Zatcepin, Ida Pesa"maa,
Sophie Haberl, Brigitte Nuscher, Gernot Kleinberger, Julien Klimmt,
Julia K Go"tzl, Arthur Liesz, Katharina Bu"rger, Matthias Brendel,
Johannes Levin, Janine Diehl‐Schmid, Jung Suh, Gilbert Di
Paolo, Joseph W Lewcock, Kathryn M Monroe, Dominik Paquet, Anja
Capell, Christian Haass. Loss of TREM2 rescues hyperactivation
of microglia, but not lysosomal deficits and neurotoxicity in
models of progranulin deficiency. The EMBO Journal, 2022; DOI:
10.15252/embj.2021109108 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220214144042.htm

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