The starting point for the research study team was a protein called TREM2. “This is a receptor on the surface area of microglia, however parts of it can remove and are then noticeable in the cerebrospinal fluid. It is understood from lab research studies, particularly in mice however also from our earlier human studies, that levels of TREM2 in the cerebrospinal fluid are an excellent indication of microglial activity. TREM2 is a kind of activity switch. As TREM2 levels increase, so do microglial protective activities,” describes Christian Haass, research group leader at DZNE and professor of biochemistry at LMU München. “For a long period of time, it was assumed that microglia primarily trigger damage in the course of Alzheimers illness, as they can fuel persistent inflammatory procedures. There is growing proof from my lab and many others that microglia have a protective result at least at the start of the illness. This hypothesis is supported by our present information.”
Estrella Morenas-Rodríguez, postdoctoral researcher in the Haass team at the time of the examination and now junior group leader at Hospital Universitario 12 de Octubre in Madrid, Spain includes: “One of the determinant points which allowed us to make our observations, which was also an obstacle, was to be able to study for the very first time the increase of the TREM2 marker longitudinally. That is, we determined the marker in a number of samples taken from the exact same individuals each or two years. With that we might much better capture the development of the various processes happening in Alzheimer ´ s illness than studying samples at just one time point.”
Conspicuous Long in Advance
People with a hereditary predisposition to Alzheimers typically develop the disease at a comparable age as their loved ones with the very same mutation who currently experience signs of dementia. Based upon this experience, the scientists were able to approximate the time up until the start of signs for all research study participants individually. In doing so, they stumbled upon early indications of the disease. “We discovered that TREM2 levels in the cerebrospinal fluid rise as early as 21 years before the estimated start of the disease,” Haass states. “We likewise observed that the much faster TREM2 increases over the years, the slower pathological occasions development in the brain that are common of Alzheimers. We can presume this from biomarkers for so-called amyloid proteins and tau proteins.”
The brain examinations utilizing MRI and PET pointed in a comparable instructions: In research study individuals in whom TREM2 levels increased rapidly, deposits of amyloid proteins that are particular of Alzheimers developed more slowly and brain volume decreased more gradually. “Besides the relationship with a slower pathological process, among our most appealing and important findings was to see how strikingly the faster TREM2 increase associated with a slower cognitive decrease in an early phase of Alzheimer ´ s disease. This has crucial implications for treatment,” Morenas-Rodríguez notes.
” We see our findings as evidence that TREM2-mediated microglial activity has a protective impact,” Haass says. “In our view, microglia end up being active as quickly as the very first amyloid proteins are deposited in the brain, a procedure, which we call seeding. To put it simply, at a really early phase of Alzheimers and that is what we and our associates at the DZNE-Tübingen also observe in animal models.”
Approach for New Therapies
For some time now, Haass and his team have been looking into drugs that specifically enhance the protective effect of microglia. Their target is the TREM2 receptor anchored on the cell surface area. “We are still in the lab phase. The existing outcomes in human beings reveal that regulating TREM2 is an appealing method to establish new choices against Alzheimers. In this specific case we studied the genetic form of the disease, we think about that our findings likewise apply to the so-called erratic variant of the illness, which is far more common. Certainly, it is crucial that treatment starts as early as possible. Todays treatments all come far too late to be truly effective,” states Haass.
Referral: “Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimers illness: a longitudinal observational study” by Estrella Morenas-Rodríguez, MD; Yan Li, PhD; Brigitte Nuscher, BSc; Nicolai Franzmeier, PhD; Prof Chengjie Xiong, PhD; Marc Suárez-Calvet, PhD; Prof Anne M Fagan, PhD; Stephanie Schultz, PhD; Brian A Gordon, PhD; Prof Tammie L S Benzinger, MD; Prof Jason Hassenstab, PhD; Prof Eric McDade, DO; Regina Feederle, PhD; Prof Celeste M Karch, PhD; Kai Schlepckow, PhD; Prof John C Morris, MD; Gernot Kleinberger, PhD; Bengt Nellgard, MD; Jonathan Vöglein, MD; Kaj Blennow, MD; Henrik Zetterberg, MD; Prof Michael Ewers, PhD; Mathias Jucker, PhD; Prof Johannes Levin, MD; Prof Randall J Bateman, MD and Prof Christian Haass, PhD on behalf of theDominantly Inherited Alzheimer Network, April 2022, The Lancet Neurology.DOI: 10.1016/ S1474-4422( 22 )00027-8.
The study consisted of examinations of the brain (symbol image). Credit: DZNE/ Frommann
Enhancing the brains defenses might assist fight the illness.
In individuals with a hereditary predisposition to Alzheimers disease, the immune cells of the brain– the “microglia”– start putting in a protective result up to twenty years before the very first symptoms appear. A group from Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and Ludwig-Maximilians-Universität (LMU) München draws this conclusion based on a research study of more than 200 volunteers, which they report in the journal The Lancet Neurology. Due to their study information, the scientists think about modulating the activity of microglia to be a promising therapeutic approach. To this end, they intend to establish drugs that target a cellular receptor called TREM2.
About one percent of all individuals with Alzheimers develop the disease as an outcome of gene mutations that can be handed down from generation to generation. As part of the international DIAN (Dominantly Inherited Alzheimer Network) observational research study, DZNE and LMU München are participating in research into this hereditary type of Alzheimers disease. The DIAN research study cohort consists of grownups who carry gene anomalies that trigger Alzheimers along with their close loved ones without mutations.
Measurements Over Several Years
For the existing research study, the team led by molecular biologist Prof. Christian Haass and neurologist Dr. Estrella Morenas-Rodríguez analyzed how signatures of microglial activation were associated with the advancement of particular biomarkers of Alzheimers disease. To this end, cerebrospinal fluid and cognition were evaluated over a duration of numerous years in 248 participants of the DIAN research study consisting of the various phases of Alzheimers illness. The volunteers were also analyzed by magnetic resonance imaging (MRI) and positron emission tomography (PET) to envision brain shrinkage and amyloid pathology– both are trademarks of Alzheimers disease.
In people with a hereditary predisposition to Alzheimers illness, the immune cells of the brain– the “microglia”– start applying a protective effect up to two years prior to the very first signs appear. As part of the international DIAN (Dominantly Inherited Alzheimer Network) observational study, DZNE and LMU München are participating in research into this genetic kind of Alzheimers illness. For the existing research, the group led by molecular biologist Prof. Christian Haass and neurologist Dr. Estrella Morenas-Rodríguez evaluated how signatures of microglial activation were related to the advancement of specific biomarkers of Alzheimers illness. To this end, cerebrospinal fluid and cognition were evaluated over a period of several years in 248 individuals of the DIAN study making up the various stages of Alzheimers disease. The volunteers were also analyzed by magnetic resonance imaging (MRI) and positron emission tomography (PET) to picture brain shrinkage and amyloid pathology– both are hallmarks of Alzheimers illness.