Neural Plasticity and Degeneration

Team leader: 

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.




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

Image icon 2024_rivera_team.png22.33 MB


  1. APP at the INP

    The last 2 weeks, several INP teams hosted M1 students for their APP (Apprentissage Par Projet). For many, it was a first experience in a research lab! Each APP is organized around a larger project (Alzheimer's Disease, Myelin, Functional imaging) and students rotate between different labs of NeuroMarseille.

    Thanks to Laurence, Christine (Team 1), Theresa, Fanny (Team 7), Naz and Marine (Team 4) for mentoring all these students!

  2. Chiara et Thaïs sélectionnées à l'action Parrainage Jeunes Chercheurs de l'association France Alzheimer

    Congratulations to Chiara Bordier (SynapTau team) and Thaïs Lestra (Neural Plasticity and Degeneration team), who have been selected by the France Alzheimer's association for their "Parrainage Jeunes Chercheurs" initiative. The objective of this program is to support young researchers throughout their three-year thesis. We are proud of them!

  3. Journée de la Recherche de la Faculté de Pharmacie 2023

    Comme chaque année la Faculté de Pharmacie de Marseille met à l'honneur ses doctorants, chercheurs et enseignants-chercheurs lors de sa Journée de la Recherche qui avait lieu cette année le 12 octobre 2023;  Au cours de cette journée les enseignants chercheurs de la faculté Pascale Barbier, François Devred, Hervé Kovacic (équipe 9), et Alessandra Pagano (équipe 8) accompagnés de  Chiara Bastiancich, Aurélie Souberan (équipe 8) et Maud Gratuze (équipe 2') étaient présents pour répondre aux nombreuses questions des étudiants de Pharmacie et/ou de Master concernant la recher

  4. Conférence "La maladie d’Alzheimer, craintes et espoirs"
    Le Cercles des Savoirs 2023

    As part of the 2023 edition of the Cercles des Savoirs program at the Roquebrussanne Open University, Dr. Santiago Rivera led a conference on Saturday September 23d entitled "Alzheimer's disease, fears and hopes".

  5. New article from NPD Team 1 published in the Journal of Neuroinflammation

    The latest article for NPD team 1 has been published this month into the Journal of Neuroinflammation.

    Membrane-type matrix metalloproteinase 5 (MT5-MMP) deficiency in the 5xFAD mouse model of Alzheimer's disease reduces brain neuroinflammation along with amyloidosis, and prevents deficits in synaptic activity and cognition in prodromal stages of the disease. In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1β)-mediated inflammation in the peripheral nervous system.

  6. Dominika during her thesis defense
    Congratulations to Dominika Pilat who is now a doctor in Neuroscience!

    To nicely end 2021 year, Dominika Pilat, student in Neural Plasticity and Degeneration Team (Team 1), successfully defended her thesis on the 16th of December. She gave a very clear, precise and comprehensive presentation highlighting the pivotal role of MT5-MMP in the neuroinflammation in an Alzheimer’s Disease model. The jury was unanimous to underline the great work Dominika accomplished during the four years she has spent at the INP leading to the publication of an article into the Journal of Neuroinflammation in which she is first author.

  7. Pedro Belio Mairal (Neural Plasticity and Degeneration team) at Neurobinar #12

    On February 22nd at 1 pm don't miss the next Neurobinar of NeuroMarseille ! You will get a chance to meet Adam Williamson, principal investigator at the INS, Gaelle Alhaddad, 2nd year PhD student at the LNC and Pedro Belio Mairal, 3rd year student in the "Neural Plasticity and Degeneration" team of INP. Gaelle and Pedro will each present the other's thesis topic and Adam will explain his work on "Non-invasive deep brain stimulation in Epilepsy using Temporal Interference". 

  8. New Post-doctoral fellow in team 1

    Neural Plasticity and Degeneration team has recently welcomed Shweta SONAWANE.

    Shweta is from Mumbai (India) she did her Ph.D. at the Biochemical sciences division of CSIR - National Chemical Laboratory in Pune (India).

    Her doctoral research was largely focused on Tau pathology in Alzheimer’s disease studying in particular the effect of glycated and phosphorylated Tau on cytoskeleton integrity as well as aggregation propensity in order to find small molecules that could attenuate Tau aggregation and prevent its glycation.



Highligthed Publications

Open Positions

Poste pourvu : 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: /

Poste pourvu : 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.


  • 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

Deadline: March 20th.

Team Publications