Neural Plasticity and Degeneration

Team leader: 
Description: 

We study the pathophysiological mechanisms that operate in Alzheimer’s disease under the scope of neuroinflammation, amyloidogenesis and synaptic dysfunctions. Understanding and fighting neurodegenerative diseases, in particular Alzheimer’s disease, is one of the most challenging endeavors of modern neuroscience. Alzheimer’s disease is the most devastating neurodegenerative disorder with a major socio-economic burden that is accentuated by the absence of effective treatments curing or slowing down its progression. Despite a variety of therapies currently under investigation, the discovery of a cure does not seem to be within reach at this point. Therefore, there is an urge in identifying new targets in the triggering/progression of the disease and understanding the underlying molecular mechanisms preceding irreversible cognitive decline. In this context, our global objective is to better understand some of the proteolytic pathways that operate at the crossroads of three major pathogenic processes tightly interconnected: neuroinflammation, amyloidogenesis and synaptic dysfunctions. Our original findings have placed some matrix metalloproteinases (MMPs) as new actors in Alzheimer’s pathogenesis because they promote neuroinflammation and amyloidogenesis, and alter synaptic transmission as well. Consequently, MMPs may become potential new therapeutic targets. The backbone of our research is therefore structured around two main objectives: i) to increase our understanding of the pathophysiological mechanisms of Alzheimer’s disease, and ii) to develop and validate innovative therapeutic strategies on the basis of newly discovered targets. We use techniques of molecular and cellular biology, biochemistry, cell and tissue imaging, pharmacology, electrophysiology and animal behavior, on in vivo andin cellulo models of the pathology, in collaboration with INP teams and worldwide. 

Public Summary: 

Our research has a twofold objective: i) to better understand why and how our brain “degenerates” with age and especially in Alzheimer's disease ii) to put in place strategies to counteract this degenerative process. With aging, our brain becomes a little rusty and we are less efficient in performing tasks that were previously easy. These functional deficits, exacerbated in Alzheimer's disease, gradually lead us on the path of dementia. Aging is certainly a major risk for Alzheimer's disease, but why some people suffer from Alzheimer's while others manage to escape it remains a fundamentally unresolved issue in most cases. Indeed, a small percentage of cases (~1%) is the consequence of well-known mutations in three genes. People carrying one of these mutations are surely subject to familial (or hereditary) forms of disease, which often appear between 40 and 60 years of age. The vast majority of cases are said to be sporadic, for which the cause, or rather the causes, are not known. In addition to aging, other risk factors likely contribute to sporadic Alzheimer's disease, including co-morbidity with other diseases (brain injury, epilepsy, ischemia, diabetes), sex, nutrition, life style, inflammation, infections, and certainly some genetic predisposition. It is therefore increasingly recognized that Alzheimer's disease results from a combination of these factors and that only one of them could not bear entire responsibility. 

In spite of recent indisputable advances on the knowledge of the biological bases of the disease, we still do not have treatments to prevent it, to slow it down or to stop it. Without treatment, the current number of 40 million patients is expected to triple by 2050, leading to an unprecedented health, economic and social crisis. These figures also provide a measure of the Herculean effort of research and the urgency of the task to be accomplished in the years to come in order to refute these gloomy estimates. Our team's contribution to this research effort is based on the original discovery that proteins generated by the brain, known as MT-MMPs, contribute to pathogenic processes and cognitive decline in animal models of the disease. As a result, we believe that MT-MMPs are potential new therapeutic targets in Alzheimer's disease. In order to consolidate this idea, our research advances on two fronts: i) we seek to better understand by which mechanisms these MT-MMPs contribute to the degeneration of our nerve cells. To this end, we use a range of state of the art techniques, as well as experimental models involving mice and pluripotent-induced stem cells (iPS) from patients with Alzheimer's disease; ii) we seek to identify chemical or natural molecules capable of modulating the pathogenic actions of MT-MMPs. We hope to add a new brick to the fight against this devastating disease affecting patients and their families, as well as our entire society. We hope that the knowledge gained from this work will also open avenues for research on other neurodegenerative diseases in which MT-MMPs would also be involved.

Research topics: 

1. Studying pathophysiological mechanisms of neurodegeneration involving neuroinflammation, amyloidosis and synaptic dysfunctions

In the wake of our previous findings, we are studying the impact of membrane-type MMPs (MT-MMPs), in particular MT1-MMP and MT5-MMP on the intracellular trafficking and processing of amyloid precursor protein (APP), in the context of their interplay with key inflammatory mediators (e.g, IL-1β, TNF-α ) and their receptors. We also use proteomic-based unbiased approaches to identify new physiological neural substrates of MT-MMPs that might be involved in their pathogenic effect. We investigate the functional consequences of these molecular interactions at the electrophysiological level, using whole-cell patch-clamp recording and calcium imaging in mixed primary cultures of neurons, astrocytes and microglia. We also study the functional impact throughout a panel of behavioral tests that evaluate learning and memory and emotional behaviors, and their correlation with pathological hallmarks in transgenic Alzheimer mice deficient for the MMPs of interest. These projects are developed in collaboration with the INP teams of Michel Khrestchatisky, François Roman.

2. Engineering tools to modulate MMP activity and/or protein-protein interactions

In order to set up targeted therapeutic strategies based on MMP modulation it is crucial to develop MMP-modifying drugs that selectively target a given MMP. Despite recent progress in the domain, this remains a challenging endeavor because the members of the MMP family share highly conserved catalytic domains. Accordingly, we implement alternative strategies in collaboration with chemists and biochemists aiming at the discovery and development of small organic molecules or neutralizing antibodies through the screening of chemical or nanobody libraries. Selected compounds are tested in vitro and in cellulo models for their ability to modulate pro-inflammatory and/or pro-amyloidogenic responses that depend on MMP catalytic activities or their interactions with substrates. Furthermore, the ability of the selected compounds to cross the blood brain barrier in in vitro models and their eventual optimization are carried out in collaboration with the biotech company VECT-HORUS, which is part of the INP. Together, these in silico, in vitro and in cellulo approaches allow selection of the hits that are further tested in in vivo models of Alzheimer’s disease.

3. Modeling Alzheimer with iPS cells for the study of pathophysiological mechanisms and target validation

Cell reprogramming has opened new avenues for the comprehensive study of neural pathophysiological mechanisms, but also for testing/validating new therapeutic targets. In collaboration with the team of Emmanuel Nivet at the INP, we implement neuronal and astrocyte cultures from iPS cells of Alzheimer’s patients that harbor familial mutations (e.g, Swedish, double APP…) or genetic risk factors (i.e, ApoE4). Using the CRISPR/Cas9 technology, we can knock out the MMPs of interest in human iPS cell lines and study the impact of such deficiency on neuron function and fate. Seemingly, human iPS-derived neural cells serve as biological platform to test MMP-modifying drugs or other relevant drugs. Also important, by working on neurone-astrocyte co-cultures, we propose a less neurocentric approach to the study of Alzheimer’s pathophysiology, which aims at deciphering the impact of astrocytes from sporadic or familial Alzheimer’s disease on neuronal function and vice versa.

 

 

Partners: 

Agence National de la Recherche        Fondation Vaincre l’Alzheimer    Association France Alzheimer    Fondation Plan Alzheimer

News

  1. Laura Garcia Gonzalez (Team 1) successfully defended her thesis

    After several years of hard and serious work, Laura Garcia Gonzalez (Neural Plasticity and Degeneration, Team 1) successfully defended her thesis last year (07/02/2020). Her project allowed to better understand the molecular mechanisms of actions of MT-MMPs (in particular MT5) involved in the pathogenesis of Alzheimer Disease (AD). Her work has paved the way for many other research projects that altogether could lead to fight against AD.

  2. Dominika Pilat (Team 1) on the Neurobinar #4 (NeuroMarseille) !

    Dominika Pilat will be presenting on the Neurobinar #4 on January 21 at 4 pm on Zoom.

    For this fourth edition, NeuroMarseille is pleased to welcome Cédric Maurange (IBDM), Dominika Pilat (INP) and Borloz Émilie (MMG). Dominika Pilat and Borloz Émilie will introduce their respective theses in a cross presentation. After a question session, Cédric Maurange (IBDM) will explain his research on genetic programmes modifying the properties of neural stem cells during development.

  3. Fondation Vaincre Alzheimer's visit at the Institute of Neurophysiopathology (INP)

    A few weeks ago, the Vaincre Alzheimer Foundation came to visit the Institute of NeuroPhysiopathology and made a short documentary on the team Neural Plasticity and Degeneration (Team 1), led by Santiago Rivera who was recently funded by the Foundation. It was an opportunity for him to thank Vaincre Alzheimer and the donors and talk about the importance of MT5-MMP, a protease that contributes to the pathophysiological mechanisms of Alzheimer’s disease and may become a potential new target.

  4. INP students presented their research work at the 14th International Conference on Alzheimer's and Parkinson's Diseases (ADPD)

    On the 26-31st March, the 14th International Conference on Alzheimer's and Parkinson's Diseases (ADPD) and related neurological disorders was held in Lisbon, Portugal. This year, almost the entire team 1 and team 6 went to this major event and our students: Laurie Arnaud, Laura García González and Dominika Pilat took the opportunity to present their work on a poster.

  5. Jean-Michel Paumier successfully defended his doctoral thesis

    Jean-Michel Paumier, former PhD student in Team 1 (Neural Plasticity and Degeneration), has successfuly defended his thesis on Wednesday the 05th of December 2018. After few hours of a nice presentation followed by many questions, the examining board congratulated Jean-Michel for his good work and granted him the diploma of doctor in Neuroscience.

  6. Santiago Rivera’s conference on Alzheimer’s disease at the University of Barcelona

    Santiago Rivera was invited to give a conference entitled “ Membrane type-matrix metalloproteinases are newcomers to the Alzheimer’s field ” in the context of the Conferences Cycle of the Institute of Neurosciences of the University of Barcelona. The conference was held on November 20th at the School of Pharmacy.

  7. Santiago Rivera’s conference on Alzheimer’s disease at the Novotel Hotel Marseille Vieux Port

    Santiago Rivera was invited to give a conference entitled “Alzheimer’s disease, fears and hopes” at the meeting of the management boards of the french Vaincre l’Alzheimer and the german Alzheimer Forschung Initiative foundations that was held on November 16th 2018 at the Novotel Hotel Marseille Vieux Port.

  8. New article from the Neural Degeneration and Plasticity team

    The latest work from the Neural Degeneration and Plasticity team, in collaboration with the BBB and neuroinflammation team of Michel Khrestchatisky: "The pro-amyloidogenic effects of Membrane-type 1-Matrix Metalloproteinase involve MMP-2 and BACE-1 activities, and the modulation of APP trafficking" is now published in the FASEB Journal (doi: 10.1096/fj.201801076R). Our data unveil new mechanistic insights supporting the pro-amyloidogenic role of MT1-MMP based on APP processing and trafficking, and reinforces the idea that MT1-MMP may become a new potential therapeutic target in Alzheimer’s disease. 

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Open Positions

The Institute of NeuroPhysiopathology (INP) in Marseille is recruiting a research engineer to study subcellular relations between APP and MT5-MMP in Alzheimer's disease

Beginning June 2021; duration 2 years; funded by the Vaincre Alzheimer Foundation

A two-year position as a research engineer is available from June 1, 2021 at the Institute of Neurophysiopathology (INP, University of Aix-Marseille/CNRS) in the team of Dr. Santiago Rivera who studies the physiopathological mechanisms of Alzheimer's disease. The project is developed in collaboration with the NeuroCyto team of Dr Christophe Leterrier also at INP.
The candidate will be involved in a project aimed at elucidating the molecular and subcellular relationships between the MT5-MMP protease and the amyloid precursor protein (APP) in neurons. For this, different approaches will be used, with protein expression by viral vectors in cultured neurons followed by live-cell, super-resolution and HCS microscopy as well as biochemical studies. Experience in one or more of these techniques, especially microscopy, will be appreciated. In addition, experience in molecular biology or data analysis with bioinformatics tools could be useful.
The candidate should have a master's degree or engineering degree in biomedical or biotechnological sciences, be enthusiastic and well-organized, have a taste for detail, a good analytical and learning capacity, be willing to work in a team and have good interpersonal and communication skills.
Applications must be written in French or English and contain: 1) A curriculum vitae. 2) A coverletter. 3) Two letters of reference.
Please send applications no later than March 10 to Dr. Santiago Rivera and Dr. Christophe Leterrier at the following e-mail addresses: santiago.rivera@univ-amu.fr / christophe.leterrier@univ-amu.fr.

Postdoctoral position at the Institute of Neurophysiopathology (INP) Marseille

A 3-year full-time postdoc position is open at the Institute of Neuropathophysiology (INP), CNRS/Aix-Marseille University to study pathogenic mechanisms of Alzheimer’s disease. The project should start in spring 2021.

The pioneering work from Dr. Rivera and Dr. Khrestchatisky’s teams suggests that metalloproteinase MT5-MMP could be a novel target in Alzheimer’s disease. The project includes the study of the mechanisms of action involved in the detrimental effects action of MT5-MMP and the identification of molecules that may antagonize such effects in cells and mice. We will use heterologous cells, iPS-derived neural cells and transgenic Alzheimer mice, as well as AAVs, conjugated peptide vectors/biomolecules and phenotypic cell/tissue analysis, using approaches of molecular and cell biology, biochemistry, advanced microscopy and histopathology.

Requirements:

  • Hold a PhD in neuroscience, biotechnology or pharmacological sciences.
  • Be highly motivated and qualified, with skills in cell and molecular biology, biochemistry and imaging analysis. Complementary knowledge in neurodegenerative diseases and skills in data management will be also appreciated.
  • Excellent oral and written communication skills in English.
  • Leadership, organizational and social skills to work in groups and independently.

The INP offers an internationally competitive environment with state-of-the-art facilities shared with the biotechnology company Vect-Horus. The postdoc will be co-supervised by Dr. Santiago Rivera and Dr. Michel Khrestchatisky and will also work in interaction with the scientific and technical staff of Vect-Horus. The project will be developed at the Faculty of Medicine, a few kilometres from the Calanques National Park and the charms of Provence.
Salary & benefits: between 24 and 30 k€/year depending on experience; full health and social coverage.
Please, send a PDF file with a CV, a cover letter indicating major interests and research experience, a list of publications and 3 reference letters or contact information of former supervisors to Dr. Santiago Rivera santiago.rivera@univ-amu.fr.
 

Deadline: March 20th.

Team Publications