Microglial Tyrobp Involvement in Tau Propagation and Associated Inflammation
Neuroinflammation in the brain may be caused in part by neurodegenerative diseases such as tauopathies and Alzheimer’s disease. The brain’s resident immune cells, called microglia, are the resident “garbage disposal cells” of the brain and thereby play key roles in any inflammatory processes. Using a novel multiscale computational approach, a team from Mount Sinai identified the protein Tyrobp as a causal regulator controlling the garbage disposal actions of microglia. To understand the role of Tyrobp in tauopathies, we generated new genetically-manipulated tauopathy-model mice that are rendered deficient for Tyrobp. Characterization of these mice will help to determine how Tyrobp modifies inflammation and the progression of tauopathy, thereby greatly influencing this field of research.
The main goal of this project is to deeply investigate the involvement of Tyrobp, and thereby microglia, in tauopathy progression associated with Alzheimer's disease (AD).
The roles of microglia in the pathogenesis of AD are highly complex. While they have long been assumed to be invariably beneficial, it is becoming clear that microglia may be either helpful or harmful, with this response occurring alternately or even simultaneously. Heretofore, through an integrative network-based approach, members of our team in Mount Sinai rank-ordered network structures for relevance to AD, and highlighted Tyrobp (also known as DAP12) as a key regulator of immune and other microglia-specific functions in AD (Zhang et al. 2013).
Using crosses between Tyrobp-null mice and APP/PSEN1 mice (an amyloid model of AD), we recently established that Tyrobp deficiency is neuroprotective in a mouse model of early AD (Haure-Mirande et al, 2017). In this proposed project, we hypothesize that Tyrobp, as a causal regulator for multiple genes involved in microglia regulation, may be a key player during the pathogenesis of tauopathies. Using in vivo and in vitro approaches, we are currently evaluating the consequences of Tyrobp deficiency and overexpression in tau mice models.
This work will advance our understanding of microglial ability, via Tyrobp, to modify and/or regulate tau pathology progression. If our hypotheses are correct, we will confirm Tyrobp as a potential therapeutic target. We already identified several compounds that down-regulate Tyrobp and the experimental validation of these predicted drugs will help us to develop new therapeutic strategies focused on Tyrobp.
About the Researcher
Dr. Mickael Audrain is a postdoctoral fellow in the Department of Neurology at Icahn School of Medicine at Mount Sinai in New York City. Following completion of his bachelor's degree in Biology and Biochemistry (Nantes University, France), he went to Paris to complete his master's degree in Neuroscience (Paris-Sud University, Paris-Saclay University, École normale supérieure Cachan, France) and his internship in Pr. Alain Prochiantz's laboratory (Collège de France, Paris, France). He then started a PhD in Neurobiology at Paris Descartes University (Doctoral School Bio Sorbonne Paris Cité) and started working on Alzheimer's disease (AD) in Dr. Nathalie Cartier's laboratory at the CEA (the French Alternative Energies and Atomic Energy Commission) in Paris area. As a PhD candidate, he used gene transfer and adeno-associated virus injections to develop and characterize new animal models of AD with a main objective: understand the early stages and the progression of the pathology. During his thesis, Dr. Audrain showed that many events appear long before classical hallmarks of AD. He used these new tools to identify early events likely to account for AD onset, and to find new early biomarkers (Audrain et al. 2016; Audrain et al. 2017). He was also involved in several projects where he used gene transfer as a therapeutic approach to overexpress multiple proteins, such as CYP46A1, sAPPɑ or IL2, and evaluate their therapeutic relevance in AD models (Burlot et al. 2015; Fol et al. 2016; Alves et al. 2017). For his postdoctoral training, he joined Professor Sam Gandy's laboratory in New York City (Icahn School of Medicine at Mount Sinai) and started working on tau and neuroinflammation with the objective of understanding the role of the central nervous immune system during the pathophysiology of AD and associated tauopathies.
My interest for science probably started during my first year in medical school before I change for a bachelor’s degree in biology and biochemistry. During these first years, I worked every summers in several geriatric services where I was thereby in contact with many elderly people with Alzheimer's disease (AD). I then moved to Paris to pursue my studies in neurobiology with a strong interest for translational research. I always liked basic research but I always needed to hang on something more concrete. It's definitely Dr. Jérôme Braudeau, who was also my mentor during my PhD thesis in Dr. Nathalie Cartier’s lab, who convinced me to continue in this field. Working on AD is challenging, not only because we have still no concrete idea how it begins in patients with sporadic forms of AD, but also because 99% (if not 100%) of clinical trials failed. Thereby, a priority that many scientists, me included, have is to find new targets of interest that could be involved in AD progression and that could be helpful to identify new early biomarkers or new therapeutic compounds. Sam Gandy is using new approaches such as RNA sequencing and iPSCs, and like the GWAS did these past few years (with APOE or BIN1 for examples), I am sure that these tools will allow us to move forward in the understanding of AD.
First published on: June 26, 2018
Last modified on: June 30, 2020