TAGLN3 as a new regulator of neuroinflammation: from a biomarker to a biotarget in Alzheimer’s disease – TRANS3

Alzheimer's disease (AD) is a neurodegenerative disease remaining incurable yet. AD is a progressive disease with a silent phase for many years before the first symptoms of dementia. Identifying an early biomarker could pave the way for the identification of new therapeutic windows and / or the development of preventive treatments. Amongst the earliest events that may underlie the onset of AD, neuroinflammation is a potent candidate. We recently identified Transgelin 3 (TAGLN3) as a new protein involved in the regulation of inflammation in human astrocytes. Our recent data showed that TAGLN3 is a protein significantly downregulated in human astrocytes carrying the genetic risk factor APOE4. We thus demonstrated that TALGN3 downregulation in astrocytes underlies the development of major inflammatory dysfunctions such as low-grade chronic inflammation and exacerbated inflammatory responses. Furthermore, TAGLN3 downregulation was confirmed in brain tissue samples from patients diagnosed with AD. Importantly, we also showed that modulating TAGLN3 can rescue astrocytes from pathogenic pro-inflammatory mechanisms. Taken together, our recent data suggest that TAGLN3 may be a molecular target of great interest to modulate astrocyte reactivity, which could lead to the development of anti-inflammatory therapeutic strategies in AD. Thus, we believe that TAGLN3 is a prime candidate for developing a new translational research project where TAGLN3 could be used both as an early biomarker of inflammatory dysfunctions underlying AD and as a therapeutic target to prevent and/or delay the development/progression of AD. Thus, this project proposes to: i) assess the potential of TAGLN3 as an early biomarker of AD; ii) test a gene therapy approach in mouse models by targeting Tagln3 in astrocytes specifically; and iii) implement a screening platform and relevant assays to screen a library of compounds and identify chemical scaffolds (hits) able to stimulate TAGLN3 expression in human astrocytes To achieve these ambitious goals, our project will leverage the complementary expertise of all three partners of the project to develop and achieve our goals. This project will implement a selective method of mass spectrometry on patient samples (CSF, blood) to validate TAGLN3 as a possible biomarker in AD. In addition, by using a lentiviral-based gene transfer method, we will modulate the expression of Tagln3 in two different mouse models that recapitulate some of the symptoms of AD found in humans. This gene therapy strategy will serve to establish the proof of concept that TAGLN3 can be targeted to modulate astrocyte reactivity, which could prevent and/or slow down the development of certain symptoms of AD. Finally, by leveraging our expertise in human induced pluripotent stem cell (hiPSC)-based models, we will establish a platform for the screening of molecules. This will include the implementation of an hiPSC-line allowing the monitoring of TAGLN3 expression in human astrocytes as well as assays developments (primary, counter-screen, secondary). This will allow us to perform the screening of a library of molecules and, ultimately, to identify Hits – i.e. chemical scaffolds capable of activating TAGLN3 expression in human astrocytes. By the end of this project, we expect that TAGLN3 will prove to be a new target of choice with multiple applications, diagnostic and therapeutic, in order to bring new possibilities in the fight against AD.