Alzheimer's: Protective immune cells active decades before symptom onset
Boosting the brain's defenses could help combat the disease

Date:
March 17, 2022
Source:
DZNE - German Center for Neurodegenerative Diseases
Summary:
In individuals with a genetic predisposition to Alzheimer's disease,
the immune cells of the brain -- the 'microglia' -- start exerting
a protective effect up to two decades before the first symptoms
appear. A team draws this conclusion based on a study of more than
200 volunteers.

In light of their study data, the scientists consider modulating
the activity of microglia to be a promising therapeutic approach. To
this end, they aim to develop drugs that target a cellular receptor
called TREM2.



FULL STORY ==========================================================================
In individuals with a genetic predisposition to Alzheimer's disease,
the immune cells of the brain -- the "microglia" -- start exerting a
protective effect up to two decades before the first symptoms appear. A
team from Deutsches Zentrum fu"r Neurodegenerative Erkrankungen
(DZNE) and Ludwig-Maximilians-Universita"t (LMU) Mu"nchen draws this
conclusion based on a study of more than 200 volunteers, which they
report in the journal The Lancet Neurology. In light of their study data,
the scientists consider modulating the activity of microglia to be a
promising therapeutic approach. To this end, they aim to develop drugs
that target a cellular receptor called TREM2.


========================================================================== About one percent of all people with Alzheimer's develop the disease
as a result of gene mutations that can be passed on from generation
to generation.

As part of the international DIAN (Dominantly Inherited Alzheimer Network) observational study, DZNE and LMU Mu"nchen are participating in research
into this genetic form of Alzheimer's disease. The DIAN study cohort
includes adults who carry gene mutations that cause Alzheimer's as well
as their close relatives without mutations.

Measurements Over Several Years For the current research, the team led by molecular biologist Prof. Christian Haass and neurologist Dr. Estrella Morenas-Rodri'guez analyzed how signatures of microglial activation
were related to the development of certain biomarkers of Alzheimer's
disease. To this end, cerebrospinal fluid and cognition were assessed
over a period of several years in 248 participants of the DIAN study
comprising the different stages of Alzheimer's disease. The volunteers
were also examined by magnetic resonance imaging (MRI) and positron
emission tomography (PET) to visualize brain shrinkage and amyloid
pathology -- both are hallmarks of Alzheimer's disease.

The starting point for the research team was a protein called TREM2. "This
is a receptor on the surface of microglia, but parts of it can detach
and are then detectable in the cerebrospinal fluid. It is known from
laboratory studies, particularly in mice but also from our earlier
human studies, that levels of TREM2 in the cerebrospinal fluid are a
good indicator of microglial activity.

TREM2 is a kind of activity switch. As TREM2 levels increase, so do
microglial protective activities," explains Christian Haass, research
group leader at DZNE and professor of biochemistry at LMU Mu"nchen. "For
a long time, it was assumed that microglia mainly cause damage in the
course of Alzheimer's disease, as they can fuel chronic inflammatory
processes. However, there is growing evidence from my laboratory and
many others that microglia have a protective effect at least at the
beginning of the disease. This hypothesis is supported by our current
data." Estrella Morenas-Rodri'guez, postdoctoral researcher in the
Haass team at the time of the investigation and now junior group leader
at Hospital Universitario 12 de Octubre in Madrid, Spain adds: "One of
the determinant points which allowed us to make our observations, and
that was also a challenge, was to be able to study for the first time
the increase of the TREM2 marker longitudinally. That is, we measured
the marker in several samples taken from the same individuals every
one or two years. With that we could better capture the development of
the different processes occurring in Alzheimer's disease than studying
samples at just one time point." Conspicuous Long in Advance People
with a genetic predisposition to Alzheimer's usually develop the disease
at a similar age as their relatives with the same mutation who already experience symptoms of dementia. Based on this experience, the researchers
were able to estimate the time until the onset of symptoms for all study participants individually. In doing so, they came across early signs
of the disease. "We found that TREM2 levels in the cerebrospinal fluid
rise as early as 21 years before the estimated onset of the disease,"
Haass says. "We also observed that the faster TREM2 increases over the
years, the slower pathological events progress in the brain that are
typical of Alzheimer's. We can infer this from biomarkers for so-called
amyloid proteins and tau proteins." The brain examinations using MRI and
PET pointed in a similar direction: In study participants in whom TREM2
levels rose rapidly, deposits of amyloid proteins that are characteristic
of Alzheimer's developed more slowly and brain volume declined more
slowly. "Besides the relationship with a slower pathological process, one
of our most important and promising findings was to see how strikingly
the faster TREM2 increase correlated with a slower cognitive decline in
an early stage of Alzheimer's disease. This has important implications
for treatment," Morenas-Rodri'guez notes.

"We see our findings as evidence that TREM2-mediated microglial activity
has a protective effect," Haass says. "In our view, microglia become
active as soon as the first amyloid proteins are deposited in the
brain, a process, which we call seeding. In other words, at a very
early stage of Alzheimer's and that is what we and our colleagues at the DZNE-Tu"bingen also observe in animal models." Approach for New Therapies
For some time now, Haass and his team have been researching drugs that specifically reinforce the protective effect of microglia. Their target
is the TREM2 receptor anchored on the cell surface. "We are still in
the laboratory phase. However, the current results in humans show that modulating TREM2 is a promising strategy to develop new options against Alzheimer's. Although in this particular case we studied the genetic form
of the disease, we consider that our findings also apply to the so-called sporadic variant of the disease, which is far more common. Certainly, it
is crucial that treatment starts as early as possible. Today's therapies
all come far too late to be really effective," says Haass.


========================================================================== Story Source: Materials provided by DZNE_-_German_Center_for_Neurodegenerative_Diseases.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Estrella Morenas-Rodri'guez, Yan Li, Brigitte Nuscher, Nicolai
Franzmeier, Chengjie Xiong, Marc Sua'rez-Calvet, Anne M Fagan,
Stephanie Schultz, Brian A Gordon, Tammie L S Benzinger, Jason
Hassenstab, Eric McDade, Regina Feederle, Celeste M Karch, Kai
Schlepckow, John C Morris, Gernot Kleinberger, Bengt Nellgard,
Jonathan Vo"glein, Kaj Blennow, Henrik Zetterberg, Michael Ewers,
Mathias Jucker, Johannes Levin, Randall J Bateman, Christian Haass,
Sarah Adams, Ricardo Allegri, Aki Araki, Nicolas Barthelemy,
Jacob Bechara, Sarah Berman, Courtney Bodge, Susan Brandon,
William (Bill) Brooks, Jared Brosch, Jill Buck, Virginia Buckles,
Kathleen Carter, Lisa Cash, Charlie Chen, Jasmeer Chhatwal, Patricio
Chrem, Jasmin Chua, Helena Chui, Carlos Cruchaga, Gregory S Day,
Chrismary De La Cruz, Darcy Denner, Anna Diffenbacher, Aylin
Dincer, Tamara Donahue, Jane Douglas, Duc Duong, Noelia Egido,
Bianca Esposito, Marty Farlow, Becca Feldman, Colleen Fitzpatrick,
Shaney Flores, Nick Fox, Erin Franklin, Nelly Friedrichsen, Hisako
Fujii, Samantha Gardener, Bernardino Ghetti, Alison Goate, Sarah
Goldberg, Jill Goldman, Alyssa Gonzalez, Susanne Gra"ber-Sultan,
Neill Graff-Radford, Morgan Graham, Julia Gray, Emily Gremminger,
Miguel Grilo, Alex Groves, Lisa Ha"sler, Cortaiga Hellm, Elizabeth
Herries, Laura Hoechst-Swisher, Anna Hofmann, David Holtzman,
Russ Hornbeck, Yakushev Igor, Ryoko Ihara, Takeshi Ikeuchi,
Snezana Ikonomovic, Kenji Ishii, Clifford Jack, Gina Jerome, Erik
Johnson, Stephan Ka"ser, Kensaku Kasuga, Sarah Keefe, William (Bill)
Klunk, Robert Koeppe, Deb Koudelis, Elke Kuder-Buletta, Christoph
Laske, Allan Levey, Oscar Lopez, Jacob Marsh, Rita Martinez,
Ralph Martins, Neal Scott Mason, Colin Masters, Kwasi Mawuenyega,
Austin McCullough, Arlene Mejia, James MountzMD, Cath Mummery,
Neelesh Nadkarni, Akemi Nagamatsu, Katie Neimeyer, Yoshiki Niimi,
James Noble, Joanne Norton, Brigitte Nuscher, Antoinette O'Connor,
Ulricke Obermu"ller, Riddhi Patira, Richard Perrin, Lingyan Ping,
Oliver Preische, Alan Renton, John Ringman, Stephen Salloway,
Peter Schofield, Michio Senda, Nick Seyfried, Kristine Shady,
Hiroyuki Shimada, Wendy Sigurdson, Jennifer Smith, Lori Smith,
Beth Snitz, Hamid Sohrabi, Sochenda Stephens, Kevin Taddei,
Sarah Thompson, Peter Wang, Qing Wang, Elise Weamer, Jinbin Xu,
Xiong Xu. Soluble TREM2 in CSF and its association with other
biomarkers and cognition in autosomal-dominant Alzheimer's disease:
a longitudinal observational study. The Lancet Neurology, 2022;
21 (4): 329 DOI: 10.1016/S1474-4422 (22)00027-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220317094758.htm

--- up 2 weeks, 3 days, 10 hours, 51 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)