Institute of NeuroPhysiopathology

BBB and neuroinflammation

The central nervous system (CNS) plays a major role in the functioning of the body and therefore benefits from a vascular system particularly adapted to its protection, the blood-brain barrier (BBB). It effectively protects the CNS from the entry of potentially neurotoxic endogenous or exogenous agents, but considerably limits the passage of pharmacological, therapeutic or imaging agents. The BBB thus appears to be a major obstacle to the treatment of CNS pathologies while the prevalence of CNS pathologies is increasing and the therapeutic area of the CNS is one of the main pharmaceutical markets. The molecular and cellular mechanisms that regulate the weakening and permeability of the BBB in a neuro-inflammatory context are still poorly understood and are central to our projects.

In addition, we are interested in receptor families involved in transport processes across the BBB and are developing vector molecules that specifically bind to these receptors to promote the transport of therapeutic and imaging agents across this barrier. These projects are carried out in partnership with the company Vect-Horus, spin-off of the laboratory.

Neural Degeneration and Plasticity

Understanding and fighting 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. Despite a variety of therapies currently investigated, 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 the underlying molecular mechanisms.

Our global objective is to better understand the role of some proteolytic pathways at the crossroads of three major pathogenic processes: neuroinflammation, amyloidogenesis and synaptic dysfunctions. Our original findings place membrane bound matrix metalloproteinases (MT-MMPs) as new actors and potential new therapeutic targets in Alzheimer’s pathogenesis because they promote neuroinflammation and amyloidogenesis, and alter synaptic transmission.

Our research is therefore supported by two main objectives: i) increase our understanding of the pathophysiological mechanisms of Alzheimer’s disease, and ii) develop and validate innovative therapeutic strategies on the basis of newly discovered targets. We use state of the art techniques of molecular and cellular biology, biochemistry, cell and tissue imaging, pharmacology, electrophysiology and animal behavior, on in vivo and in cellulo models of the pathology, in collaboration with INP teams and worldwide.

NOSE. Nasal Olfactory Stemness and Epigenesis

Our team co-discovered and characterised the adult human and rodent nasal olfactory stem cells. We use these unique cells to investigate the molecular mechanisms underlying the symptoms of Autism Spectrum Disorders. An abnormal expression of an enzyme (MOCOS) was unveiled in patients’ stem cells. We now assess the role of this enzyme during brain development and try to identify drugs that restore a physiological expression of MOCOS.

The team also uses human olfactory stem cells for repairing the pathological brain. We performed studies based on the transplantation of olfactory stem cells in models of amnesia and Alzheimer’s disease. We are currently devising new protocols for differentiating stem cells into dopaminergic neurons. The team is engaged in translating our basic research into clinical applications. Trials dedicated to nerve and bone repair are in preparation.

In parallel, in order to improve functional recovery, the team assesses the immuno-modulatory and neurotrophic roles of vitamin D. Preclinical studies on animal models of nerve section, paraplegia and Alzheimer’s disease are encouraging.

Genes, Rhythm and Neurophysiopathology

The daily change of day and night due to the Earth's rotation along its axis, has led all living organisms on this planet to develop internal clocks called circadian clocks that allow them to adapt and anticipate this daily change in the environment.

The team's research focuses on the molecular mechanisms of these circadian clocks, particularly those involving long non-coding RNAs.

Knowing that profound alterations in our biological clock can be observed in patients suffering from pathologies of the central nervous system, the team's mission is also to study the role played by genes, proteins and long non-coding RNAs involved in the functioning of the circadian clock, in brain diseases, in particular neurodevelopmental diseases such as Prader-Willi syndrome.

Neurobiology of mnesic processes

The team is working on changes in the neurobiological substrate during learning and memory processes, including in pathological conditions. The underlying hypothesis is that durable memory traces proceed from the marking of specific neural networks. These synaptic plasticity mechanisms result from molecular and structural changes that largely remain to be identified and integrated at the behavioral level.

In mice, we developed a new olfactory test, “the tubular olfactory maze” where we test the effect of molecules or genetic manipulations on different memory subcategories. We observed specific structural changes in the dorsal and apical dendrite density of CA1 pyramidal cells of the hippocampus, specifically amplified by a 5-HT4 receptor agonist known for his promnesic effect. We are currently using this test in a model of Alzheimer’s disease (5XFAD transgenic mice).

With the same aim of creating animal models to study memory, we developed a deferred task paradigm in mice that highlights specific deficits as observed in patients with frontal lobe syndrome, including a perseveration behavior.

Finally, with a view to overcome the memory deficits in our amnesic syndrome models in mice, we performed intra-hippocampal transplantation of adult stem cells from the human olfactory mucosa. Following these grafts, we observed a recovery of memory capacity and the ability of these cells to acquire a neural or glial phenotype. We are currently conducting autologous grafts in rat models of amnesia and spinal cord injuries.

Neuro-inflammation and multiple sclerosis

The « Neuroinflammation and Multiple sclerosis » team is an emerging research team issued from the « BBB and Neuroinflammation » team. It is coordinated by Sophie Desplat-Jégo, MCU-PH, MD, PhD , specialized in medical immunology. SDJ has developed a research topic on the role of the cytokine TWEAK, member of the TNF family during neuroinflammation especially in the pathological context of multiple sclerosis (MS) and her group has generated reference articles that describe the deleterious effects of TWEAK in the CNS during MS and its animal model, EAE. In the last years, the TWEAK project has focused on the study of biological effects of TWEAK on the properties of the BBB. In the coming years, the team will pursue studies on neuroinflammation and involvement of TWEAK in MS.

Stem Cells, Disease Modeling and Neuroregeneration

Our research team is studying the molecular and cellular mechanisms driving pathogenic processes in the human brain, with specific focus on two diseases for which the lack of treatments urge the need for new insights: 1) the Alzheimer’s disease (AD); and 2) brain tumours, namely gliomas.

Permanent questioning is the seed of Science. As such, our research group is wondering: How genetic risk factors impact on AD pathogenesis? Is neuroinflammation one of the driving forces in AD pathology? Is the astrocyte a pivotal cellular determinant in AD? Noteworthy, we are also working on the validation of new therapeutic targets in AD. Besides, we are also developing human cell-based models aiming to recapitulate gliomagenic processes, allowing the study of the mechanisms at stake and offering the possibility to screen/test therapeutic molecules against brain cancer cells.

To quench our thirst for new knowledge, our team is leveraging on innovative and cutting-edge strategies. The core of our research relies on the development/use of cell reprogramming-based disease modelling strategies (human induced pluripotent stem cells especially) as well as genome editing technologies (CRISPR-Cas9-based); which we combine with a battery of techniques (molecular and cellular biology, biochemistry, cell imaging, pharmacology) to address our questions.

NeuroCyto: the neuronal cytoskeleton in physiology and disease

“NeuroCyto: the neuronal cytoskeleton in physiology and disease” is a lab that started in 2017 and is part of the Neuropathophysiology Institute (INP, CNRS-Aix Marseille University UMR 7051) in beautiful Marseille, France.

The team currently has six members, and we welcome trainees all year long. Motivated students are always welcome to contact us! We aim at building a thriving team to make the best possible science by nurturing openness, exchange, and the excitement of discoveries big and small.

At NeuroCyto, we want to understand how neurons are organized at the cellular level. How do they differentiate, then build and maintain their complex arborization? How do they establish and conserve their polarity, with the axon and dendrites allowing to send and receive signals? Numerous processes contribute to this organization: elaboration of the cell architecture (thanks to the cytoskeleton), protein transport inside the cell (with diffusion and motor proteins), segregation into distinct compartments (such as axon, synapses, dendritic spines…). The NeuroCyto team applies advanced microscopy techniques to directly observe molecular assemblies at the nanoscale in neurons, revealing how they organize the neuron and shape its physiology.

Gliomagenesis and microenvironment

Our GlioME team develops projects to better understand human glioma biology, to identify new targets, and to evaluate promising anticancer therapies using appropriate cellular and pre-clinical models.

Gliomas are the most common intracranial tumors in humans. The most malignant is glioblastoma (GBM, grade IV), with an incidence of 3–5 out of 100,000 persons in Western countries. GBs are lethal tumors and even optimal surgical resection, followed by chemotherapy and irradiation, results in a median survival of about 12–15 months. We trust that a comprehensive understanding of glioma cell-of origin as well as the intricate micro-environmental landscape of these tumors will result in the development of novel therapeutic strategies.

Therefore, our team focused on:

1. Setting up performing preclinical glioma models and identify new targets

2. Identify glioma biomarkers and participating to clinical trials

We are also involved in basic science consortia dedicated to nanoparticles design and development for brain tumor treatment.

Cytoskeleton and Neurophysiopathology

We aim to identify biomarkers and new pharmacological compounds active for cancer and neurodegenerative diseases with specific focus on tubulin cytoskeleton and Tau protein, Rho-GTPases, integrins, aggregative proteins and redox signaling

Oligodendroglial Cell Lineage in Aging and in Disease

In the central nervous system, oligodendroglial cells represent an abundant cell population with critical functions, as they sense, regulate, and provide insulation and trophic support to neurons. From oligodendrocyte progenitor cells to myelinating oligodendrocytes, the oligodendroglial lineage is therefore crucial for normal neurological functions, such as brain plasticity. With age, in parallel with a profound decline of cognitive abilities, oligodendroglial capacities have been shown to decline. Defective myelination has been attributed to age-related epigenomic, transcriptomic and phenotypic changes in adult oligodendroglial cells, affecting their myelinating properties.

Our team addresses: How aging affects oligodendroglial cells in the central nervous system? How can it directly impact brain cognition in aging and in neurodegenerative diseases? Can we rejuvenate old oligodendroglial cells?

By challenging our aging-like oligodendroglial-specific mouse model and age-related disease models with behavioral tests, we address the role of oligodendroglial cells in aging and in psychiatric and neurodegenerative diseases. We use transcriptomic approaches and in vitro assays to identify and characterize the molecular mechanisms that regulate neuro-oligodendroglial interaction, from a specific oligodendroglial point of view. We are also leveraging epigenetic activators, in combination with non-invasive delivery tools, to reactivate cells in our aging and disease models.

Angiogenesis and tumor microenvironment

Glioblastoma (GBM) is a devastating brain tumour characterized by local invasion, microvascular proliferation, and therapeutic resistance. The highly infiltrative nature of glioma cells makes complete surgical resection unlikely, and 90% of tumors recur. High-grade gliomas are among the most angiogenic of all tumors. Adrenomedullin (AM) is a 52 aminoacid C-terminal amidated peptide widely expressed in a variety of tumor types and was shown to be mitogenic for many human cancer cell lines in vitro. AM binds to and mediates its activity through the G protein-coupled receptor calcitonin receptor-like receptor (CLR), with specificity for AM being conferred by the receptor activity modifying protein -2 (RAMP2) and -3 (RAMP3).

The genetic ablation of AdM, calcrl, Ramp2 or the enzyme responsible for functional AM amidation, peptidylglycine α-amidating monooxygenase (PAM) all result in midgestational lethality associated with severe interstitial edema and cardiovascular defects. In vivo studies highlight the significance of AM as an important factor to promote tumor growth and to affect the tumor microenvironment by inducing pathologic angiogenesis and lymphangiogenesis. Accumulating studies suggest a new role for AM as a cross-talk molecule that integrates tumor and microenvironment stroma cells underlying promotion mechanisms to facilitate angiogenesis and tumor growth.

Several in vivo studies have shown a regression of tumor neovessels and growth upon the treatment with neutralizing AM antibodies, AM receptor antagonist, or AM receptor interference. These findings highlight the implication of AM in the progression of tumor growth and angiogenesis, suggesting that targeting the AM system may be a useful therapeutic strategy in brain cancer. Therefore, understanding the molecular mechanisms by which AM can determine the integrity of tumor neovessels will be the main focus of our research with the use of GBM as model to pursue our projects.

Vect-Horus

VECT-HORUS is a biotechnology company that designs and develops peptide-based vectors that facilitate the delivery of drugs or imaging agents into organs, notably into the brain, and to tumors. The vectors target receptors involved in “Receptor Mediated Transport” (RMT, a physiological system for the transport into cells of endogenous substances). By combining drugs or imaging agents to its vectors, VECT-HORUS allows them to cross biological barriers that restrict access to their target, notably the blood-brain barrier (BBB).

For more information, visit their website.