CV Science

Nicolas SERGEANT Diagnostic and therapeutic development for neurodegenerative disease

Course and current status

Between year 1994 to 2001, With my mentor André Delacourte we described the biochemical pathway or “natural history” of neurofibrillary degeneration and characterized the biochemical signatures of Tau aggregates in Tauopathies including also a pioneered biochemical description of neurofibrillary degeneration in myotonic dystrophy (Vermersch et al., 1996; Delacourte et al., 1998; Delacourte et al., 1999; Sergeant et al., 1999; Sergeant et al., 2001). To that purpose, I have developed Tau specific polyclonal antibodies and a 2-D gel method to analyze Tau proteins from Tau aggregates. We also contributed using this approach to demonstrate that Tau proteins in aggregates were hyper- and abnormally phosphorylated even when compared to the physiological phosphorylation status of Tau proteins obtained from fresh human brain tissue (Sergeant et al., 1995). 

In the meantime, I was also interested to complete this “natural history” study in the autopsy brain collection of more than 100 individuals, with the analysis of the amyloid pathology. (Delacourte et al., 1999; Sergeant et al., 2002; Sergeant et al., 2003). For having a complete overview of APP metabolites, polyclonal antibodies were developed and 2-D gel method for the analysis of Ab peptides from human Ab deposits extracted in formic acid. We were, together with neuropathologist to suggest a synergic relationship of Tau and Amyloid pathology where Tau pathology spatiotemporal progression was burden weighted by the amyloid pathology (Delacourte et al., 2002). We also characterized the truncated variants of Ab peptides including the 3-pyroGlutamate Ab which may further promote Ab aggregation and toxicity (Sergeant et al., 2003). 

These studies of the natural history of AD lesions in the human disease pioneered the concept that therapeutic intervention should consider both lesional processes and their unknown mechanistic relationship. Based on the burden weight of amyloid pathology to the Tau pathology progression the hypothesis made in 2000 was to correct the defective metabolism of APP we characterized in the human AD brain, and more especially the loss of APP metabolites together with the increase of Ab_1-xproduction (Sergeant et al., 2002), although the latter was not innovative.

What could restore or stabilize the APP metabolites, and more especially the carboxy-terminal fragments (APP-CTFs) and intracellular domain of APP? We developed immunological tools, SY5Y neuroblastoma stably expressing the human wild-type APP⁶⁹⁵ and initiate a collaboration with chemist of the Lille University, headed by the President of Lille University, Christian Sergheraert, who developed a whole library of chloroquine derivatives to find anti-paludism drug for the treatment of patient resistant to chloroquine. Why chloroquine ? This was promoted by the work Paul Greengard who first showed that chloroquine stabilizes APP-CTFs and precludes Ab production (Caporaso et al., 1992; PMID: 1549591). This is the starting point of drug development in Lille with the first family of molecules derived from piperazine and among which, Ezeprogind has this ended a clinical Phase II for a rare Tauopathy, Supranuclear Gas Palsy (Alzprotect company, based in Lille, www.alzprotect.com). We are now at the fifth series of drugs all sharing the similar properties against both Amyloid and Tau pathologies in mouse models of both amyloid and Tau pathologies, astrogliosis and neuroinflammation (Sergeant et al., 2019; Tautou et al., 2021), including also more than 5 patents (Patents in F). Our molecules have shown some interesting therapeutic potentials against both lesional processes of AD and provide insights for the proof of concept that small drugs can be effective against Tauopathies including AD. Although several biological properties of these molecules have been suggested without knowing the target of our molecules, it now appears essential to identify and characterize this target to better understand the mode of action and more importantly envision to develop novel target-directed assays for high throughput screening including FDA approved drugs thus giving an opportunity to find and reposition existing drugs for therapies of neurodegenerative diseases.

Other significant contributions include the development of a decoy gene therapy for myotonic dystrophy, which derived from more than twenty years of research focusing on the mechanism leading to Tau mis-splicing in myotonic dystrophy brain, heart, and muscle. Have demonstrate that this mechanism was driven by two splicing regulatory paralogues MBNL1 and MBNL2, the molecular structure-activity relation of MBNL activity led to the discovery of a C-terminal truncated MBNL protein that kept its RNA binding property but lose its splicing activity, then acting as a decoy MBNL factor (Tran et al., 2011). The proof of concept for a gene therapy has been made for muscle, since transgenic mice model of brain impairment in myotonic dystrophy were missing at that time. Nonetheless, we showed that this MBNL-decoy protein, is nontoxic, nonimmunogenic and correct the molecular defects and restore the muscle function using a gene therapy (Arandel et al., 2022).

Finally, because in my expertise in proteomics of aggregated proteins, in collaboration with the head of the fertility department of Lille University Hospital, the challenge proposed was to perform a differential analysis of human sperm proteome for healthy men having idiopathic infertility, meaning that all sperm parameters are normal, but procreation was not possible. We discovered biomarkers of idiopathic infertility, including proAKAP4 protein and created a MedTech and immunological assays to provide the human and animal market with the first molecular assay of sperm quality, long-term motility and fertility (www.4biodx.com).

Scientific summary

Nicolas Sergeant is a full-time research director at Inserm UMRS 1172 Alzheimer & Tauopathies group. He is committed to understand the mechanisms leading to neurodegeneration, unravel biomarkers and therapeutic targets for a family of neurological disorders named Tauopathies. He graduated in Biology of Aging in 1994 at the University of Paris Diderot VII and focused his Ph.D. on characterizing the biochemical signature of neurological disorders all having in common a neurofibrillary degenerating process made of different sets of microtubule-associated Tau protein isoforms. He joined Inserm in 2000 as a full-time researcher and started to investigate the relationship between the lesional processes of AD, namely the amyloid and Tau pathology. He developed all methods and tools to understand, find biological markers and therapeutic perspectives to correct or slow down neurodegenerative diseases, including Alzheimer’s Disease and Myotonic Dystrophy. He developed novel proteomics methods to analyze protein aggregates, biology system for drug screening and structure activity relationship, developed poly and monoclonals as well as transgenic models for the study of Tau splicing also used for Tau seeding and propagation and expertise in medicinal chemistry, therapeutic strategy design and immunological assays development together with basic biochemistry and molecular biology skills. He has eleven patents and contributed with Pharmaceutical companies (Alzprotect, Sanofi, Innogenetics, Pfizer, Biogen, Servier …) to develop biomarkers, small drugs molecules against Tauopathies and AD – one, Ezeprogind who recently succeed the clinical Phase II for Supranuclear Gas Palsy – and a gene therapy for myotonic dystrophy; a neuromuscular disorder belonging the family of RNAopathies which associates a mis-splicing of Tau, the development of neurofibrillary degeneration and cognitive deficits. Nicolas Sergeant has published more than a hundred articles and he his member of operational committee of Foundation Plan Alzheimer, member of the Scientific committee of l’Association France Alzheimer, member of the AFM task force on myotonic dystrophy as well as member of the scientific committee of the international myotonic dystrophy congress and associate editor for Frontiers in Neurology and Exploration of Neuroprotective Therapy Journal.