Articles written in English

Specific regions of the brain are atrophied in neurodegenerative diseases, however, physiological differences from one patient to another make it difficult to predict the progression of neurodegeneration in a specific individual.

An important theory of the progression of neurodegenerative diseases is that misfolded pathological proteins move from one neuron to another via trans-synaptic propagation. Seeley and his colleagues, but also others like H Braak have previously proposed, based on this idea, that the disease begins in an area of ​​the brain, the epicenter, and spreads into new, functionally connected regions.

Most of the information in this regard came from cross-sectional data. It remained to be seen whether such a model predicted longitudinal atrophy in individual patients. In the present study, the authors sought to do just that in patients with frontal variant behavioral dementia (bvFTD) or the semantic variant of primary progressive aphasia (SVPPA), two forms of frontotemporal dementia with schemas distinct from atrophy. They hypothesized that, in a particular disorder, individual patients would have distinct epicenters that would dictate differences in the overall progression of the disease.

In general, epicondensons overlap in patients with the same syndrome. In patients with bvFTD, they most often resided in the anterior cingulate cortex and fronto-sinus cortex. In people with svPPA, the epicenter tended to be close to the anterior temporal lobe. Even in this case, the exact location of the epicenters still varied considerably from person to person. Interestingly, although these epicenters have always shown signs of atrophy, they were not necessarily the areas of greatest loss of volume. Within each disease, patterns of atrophy differed considerably from person to person.

Scientists led by Jesse Brown and Bill Seeley of the University of California, San Francisco, used a single structural MRI in 72 patients with frontotemporal dementia to predict which regions of their brain would succumb to the disease.

They were able to determine the probable origin of the disease - its epicenter - and used functional connectivity maps to extrapolate areas that may subsequently atrophy during disease progression. Their predictions seem indeed correlated with the loss of brain volume in the following years. the authors suggest that this method provides an individualized biomarker for clinical trials and also for early diagnosis. Brown and colleagues show that the key biology at play in neurodegenerative diseases involves the functional physiology of large-scale brain networks that support mental functioning. As in previous studies, the methods used in this study do not differentiate competing patterns of networked neurodegeneration.

To identify areas that could atrophy as the disease progressed, researchers developed a forecasting model that took into account three factors: the functional link of a region to the epicenter, the narrowing of its closest neighbors and the loss of reference volume. From there, the researchers determined the probable atrophy patterns of 42 volunteer patients of bvFTD and 30 patients with svPPA. These participants then performed an average of three additional separate analyzes of six to 14 months, and the researchers compared the expected results to the actual loss.

Two aspects of the study are particularly noteworthy. The first is the idea of ​​a model of personalized prediction of longitudinal atrophy of the brain, based on the hypothesis of trans-neuronal propagation. The second is the introduction of a concept called "nodal risk", which is a measure of the regional risk of future atrophy based on the degree of basic atrophy in highly functionally connected regions. Compared to previous group-level approaches, an individualized metric of the rate and directionality of impending brain atrophy has important potential ramifications for clinical practice and clinical trials. For example, because cerebral atrophy is closely related to the clinical progression of the disease, this method based on connectivity can be useful for the prognosis of various neurodegenerative diseases. In addition, the placebo and treatment groups could be carefully compared to the atrophy rates expected during clinical trials.

In addition, identifying a group of "fast progressors" may allow for more effective screening of drug candidates (ie, shorter duration and fewer people).

The researchers found that the rate of volume loss differed across brain regions. For the most part, these patterns of atrophy were quite similar, with a correlation coefficient of 0.65. For 16 patients, including 13 with bvFTD, the model did not predict volume loss, with an average correlation coefficient of -0.04. Most of these patients had limited initial atrophy and a confused epicenter. The strongest contraction occurred not in the epicentres themselves, but in their first-degree neighbors. Perhaps the epicenter had already degenerated as much as it would, while the first-degree neighbors were just beginning, the authors said. "This has fundamental implications for clinical trials that would use indexes derived from imaging as a result," wrote Bejanin. "The best areas for evaluating the effect of disease-modifying drugs should not be those that are primarily affected by the disease, nor the most atrophied, but those most connected to these areas."

The method requires important information about the emerging neurodegenerative pattern, which may hinder application in the early stages of the disease. It is not yet refined enough to be used in clinical trials. In this study, grouped data on the functional connectome of a group of healthy people were used to predict connectivity, but using a patient's own connectome would likely improve predictions. With greater accuracy, this model could provide a proof-of-principle indicator for early-to-intermediate-stage clinical trials. For example, if a therapy causes less atrophy than expected, it could encourage stakeholders to conduct a confirmatory test.

However, although it is highly correlated, atrophy is not equivalent to the underlying pathology. Thus, some of the direct effects of the pathology on cognition and / or behavior (i.e., mediated by atrophy) may not be captured.

a more distant goal is to predict enough atrophy to predict the symptoms that patients may expect in the future. This model may be useful in other neurodegenerative diseases, including Alzheimer's disease, although the dual proteininopathy of Aβ and Tau protein is likely to make the situation more complicated.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Living organisms use energy in a radically different way than immune cells in vitro.

For years, scientists have used cells grown in Petri dishes to study the metabolic processes that fuel the immune system. But a new article suggests that living organisms use energy in a radically different way from immune cells in vitro.

The scientific consensus since Warburg's work is that immune cells, called T cells, convert glucose into energy to fuel cellular function. In fact there are different mechanisms by which a cell can get energy, the so-called metabolism or also respiration.

How do the cells get energy?

On the one hand, we distinguish anabolism, which represents all the biosynthetic pathways of cellular constituents, and on the other hand, catabolism, which represents all the pathways of degradation of these cellular constituents into small molecules to release them. energy by oxidation or to rebuild other cellular constituents.

Catabolism can be differentiated between aerobic and anaerobic respiration. Aerobic respiration includes glycolysis, oxidative decarboxylation of pyruvate, citric acid cycle, oxidative phosphorylation.

The main degradation pathway is glycolysis, where sugars such as glucose and fructose are converted to pyruvate and generate ATP. Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA by aerobic glycolysis (with oxygen) and introduced into the citric acid cycle.

Lipids are catabolized by hydrolysis to free fatty acids and glycerol. Glycerol enters glycolysis and the fatty acids are decomposed by beta-oxidation to release acetyl-CoA, which is then introduced into the citric acid cycle.

There are two important microbial methane formation pathways, by carbonate reduction (respiration) and acetate fermentation.

Warburg hypothesized that cancer growth is caused by energy-generating tumor cells (such as, for example, adenosine triphosphate / ATP) primarily through anaerobic degradation of glucose (called fermentation or anaerobic respiration). This contrasts with healthy cells, which primarily generate energy from the oxidative decomposition of pyruvate. Pyruvate is a final product of glycolysis and is oxidized in mitochondria. Therefore, according to Warburg, cancer should be interpreted as mitochondrial dysfunction.

For multicellular organisms, during brief periods of intense activity, muscle cells use fermentation to supplement ATP production from slower aerobic respiration.

What was discovered?

Jones and colleagues found that T cells in a living system use glucose as a building block for DNA replication and other maintenance tasks, in addition to converting glucose into raw energy. They also discovered that the way T cells treat glucose evolves during an immune response. The metabolism of glucose in T cells changes dynamically during an immune response. Glucose-dependent serine biosynthesis promotes T-cell proliferation in vivo.

enter image description here

This suggests that T cells can use resources differently in the body when they are fighting a bacterial infection such as Listeria or a disease like cancer.

Naïve CD8+ T cells differentiating into effector T cells increase glucose uptake and transition from resting metabolism to anabolic metabolism. Although much is known about the metabolism of cultured T cells, the way in which T cells utilize nutrients during the in vivo immune response is less well defined. The researchers therefore combined the bioenergetic profiling and 13C glucose perfusion techniques to study the metabolism of CD8+ T cells responding to Listeria infection.

In contrast to the in vitro activated T cells, which exhibit Warburg metabolism, physiologically activated CD8+ T cells exhibited higher levels of oxidative metabolism, higher bioenergetic capacity, differential pyruvate utilization, and high 13C carbon flux. glucose to the anabolic pathways, including the biosynthesis of nucleotides and serine. The glucose-dependent serine biosynthesis induced by the Phgdh enzyme was essential for the expansion of CD8+ T cells in vivo.

Our immune cells do not work in isolation

"It's like watching animal behavior in a zoo or in the wild - our immune cells do not work in isolation - they work with a host of other cells and factors that influence how and when they are used. of energy, "said Russell Jones, Ph.D., lead author of the study and head of the Metabolic and Nutritional Programming Group at the Van Andel Institute. "Understanding cell metabolism is a crucial part of therapeutic development, and our results reinforce the need to study these cells in an environment as close as possible to nature."

The findings have profound implications for how scientists study the complex and interconnected systems that underlie health and disease and how they translate this information into new diagnostic and treatment strategies.

"Immune cells react much more dynamically to infections and diseases than we previously thought," Jones said. "For a while, we're at a stage of metabolism research, it's like we're in the dark under a lamppost, we could only see in front of us, and these results will help us better understand this. which immune cells need for optimal function. "

Which suite will be given?

The results were made possible by a new method developed in consultation with collaborator Ralph DeBerardinis, MD, Ph.D., who allowed Jones and his colleagues to map how T cells use nutrients in living organisms. They have developed a 13C infusion method to study T cell metabolism in vivo

"In the future, this new mapping technique will be invaluable in pursuing studies of specific diseases," said Eric Ma, Ph.D., lead author of the study and a postdoctoral researcher in the field. Jones's laboratory.

In the future, the team plans to design human studies to measure how T cells use glucose and other nutrients when they respond to pathogens or other diseases such as injuries or diseases such as cancer.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

History of brain organoids

Cerebral organoids have provided a means of generating complex, three-dimensional and in vitro models of human neurons that summarize, in part, neuronal diversity and aspects of the physical architecture of the developing brain, such as stratification.

The researchers led by Lancaster generated the first cortical organoids in 2013. They seeded stem cells in a three-dimensional matrix with a nutrient bath. Within a month, the cells have differentiated and formed small structures of a few millimeters, looking like miniature brains. These cell layers mimicked structures such as the hippocampus and cerebral cortex. Without blood supply, however, the neurons at the center of these organoids decayed and eventually died.

The brain organoids as models

The organoids of the human brain have become a promising model for the study of neural development and neurological disorders, including Alzheimer's disease. This model has enormous potential for testing therapeutic agents and determining their permeability across the blood-brain barrier.

However, it remains difficult to generate an authentic model that summarizes the complex structure and function of the human brain. Brain organoids can not fully capture the cellular diversity of the brain. The absence of microglia and blood vessels is particularly troublesome, if one wants to apply these organoids to the study of Alzheimer's disease. The absence of a vascular system causes the organoids to become limited in size and contain a largely necrotic nucleus due to the inability of the nutrient fluid to enter the center of the structure.

What is the contribution of Cakir and his colleagues?

Cakir and his colleagues established an organo-cerebral model with a vascular-like system that works in implanted mice. This system is unique in many respects compared to previously published brain organoids.

They generated vascularized human cortical organoids by expressing an endothelial transcription factor. They discovered that such human cortical organoids developed a complex vascular network. The vascularized human cortical organoids were in good health compared to nonvascularized equivalent organoids.

enter image description here

When the authors compared cellular transcriptomes, they found that vascularized human cortical organoids expressed more mature neuronal markers, as well as markers of other cell types, particularly those involved in the formation of neurovascular units. including tight junction markers, astrocyte and pericytic proteins, and transporters.

Application to Alzheimer's disease

In addition, the treatment of vascularized human cortical organoids with oligomeric Aβ42 resulted in tight junction malformation and disruption of the blood-brain barrier, indicating that the blood-brain barrier structure responds to exogenous factors. The vascularized human cortical organoids were grafted into mice and formed functional vascular connections with the host mouse.

With respect to Alzheimer's disease, the authors have shown that oligomeric synthetic Aβ preparations selectively perturb the permeability of the blood-brain barrier in their vascularized human cortical organoids. An interesting question is: Is it possible that high levels of oligomeric Aß could compromise cerebrovascular integrity and allow therapeutic biological products and small molecules to pass freely across the blood-brain barrier of patients with Alzheimer's disease?

How to apply brain organoids technology to the study of neurodegenerative diseases?

First, given the known variability among organoids, future studies should address the fundamental issue of reproducibility and functional homogeneity. In addition, the current method for modeling fetal brain-like organoids may be somewhat limited for summarizing a mature brain environment. The vasculature of the adult brain is much more complex, including in the perivascular spaces, which contribute to the elimination of toxic solutes such as Aβ.

The incorporation of iPSC microglia into organoids (Abud et al., 2017), paves the way for the creation of complex, multicellular and human in vitro models to study the mechanisms of non-cellular autonomic diseases in Alzheimer.

It will be very interesting now to investigate whether the blood vessels are able to constrict and dilate, if the pericytes can contract and relax, if the vascularized human cortical organoids would be useful for studying neurovascular coupling, if there is venous and arterial flow and many others questions. The next years of research using vascularized brain organoids will provide more answers and will undoubtedly enable many breakthroughs in the cerebrovascular field.



Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

I did published a book on ALS research:

Caveats: I am not a doctor, nor a scientist and English is not my mother-tongue.

Here are some take home points:

  • Scientists are obsessed by SOD1 (2% of all ALS cases) as a model for ALS. However there is overwhelming evidence this is a fruitless pursuit.

  • There are nearly no treatments:

    • For all pALS, a very imperfect treatment is Nurown, but it exists!
    • For SOD1 pALS (2% of all cases), there are two treatments that are in clinical trials.
    • For the other (98%) pALS there are no drugs in the pharmaceutical pipeline. However for most pALS (TDP-43 / 95% of all cases) there are genetic therapies that have recently been published by scientists, but if no one tries to defend them, it will take another 10 years before they are marketed.
  • The ALS research is bizarre, scientists often contradict colleagues but nobody seems to care. The consensus still cites theories that have been disproved since decades, like glutamate excitotoxicity. ALS is certainly not one homogeneous disease, but it is still treated as such by scientists. Animal models of ALS have little value in translation of drugs to humans, but moreover often ALS research is done on insects (that have an exoskeleton), or even on unicellular organisms. There is no formalism anywhere, little effort to falsify any thesis.

What can you expect to find in this book:

  • A brief description of ALS and its common variants (PLS, PMA, etc): ~7 pages

  • A description of the cell in general, from an ALS point of view : ~15 pages

  • A strong focus on the neuronal cells, again with ALS in mind: ~34 pages

  • The main themes in ALS research (dying forward, excitotoxicity, virus, etc): ~40 pages

  • Main achievements of ALS research (SOD1, TDP-43, discovery, etc): ~113 pages

  • A focus on clinical trials and 28 drugs: ~37 pages

  • Different kind of therapies (MSC, ASO, etc): ~20 pages

  • A possible new therapy for ALS (if only a company had the will to investigate it!): ~20 pages

  • Futures therapies that are researched now (creating or grafting new neurons): ~17 pages

This is not an easy read, so I tried to explain terms, provide a large section on the neuronal cell at the beginning, and wrote 276 footnotes.

There are no speculations, nor pseudo scientific babble. I am not overly kind either with ALS scientists, clearly they can do much better.

Jean-Pierre Le Rouzic

My book on ALS research

Alzheimer's, FTD, bvAD and bvFTD

The signs of Alzheimer's disease, which is characterized by a selective amnesia, for example of his relatives, are well known. Fronto-Temporale Dementia (FTD), it is associated with significant changes in social and personal behavior, apathy, blunted emotions and language deficits. The FTD shares gene mutations with ALS. The behavioral variant of frontotemporal dementia (bvFTD) is characterized by changes in social behavior and behavior, with loss of social awareness and insufficient control of impulses.

How to differentiate bvAD from bvFTD?

Singleton and colleagues have shown that Alzheimer's disease, which typically leads to amnesic dementia, may also have behavioral variants (bvAD) and that the phenotype determinant is the anatomy of neurodegeneration.

enter image description here

In a small percentage of people with Alzheimer's disease, early behavioral changes, such as disregard for social norms or loss of empathy, may lead physicians to misdiagnose a behavioral variant of front-line dementia. temporal. How can they better distinguish this variant of Alzheimer's disease? The diagnosis between bvAD and bvFTD is clinically very difficult without imaging.

While structural MRI does not make a significant distinction between bvAD and typical Alzheimer's disease, metabolic PET shows a decrease in the activity of frontense and anterior default mode networks in bvAD, similar to bvFTD .

What is a default neurology network?

In neuroscience, the default network (DMN) is composed of interacting brain regions, whose activity is highly correlated with each other and distinct from other brain networks.

Initially, it was assumed that the default mode network was most often active when a person did not focus on the outside world and his brain was dormant, such as daydreaming or mental observation. However, it is now known that this can contribute to experience elements related to the performance of external tasks. He is also active when the individual thinks of others, thinks of himself, remembers the past and prepares himself for the future. Although the DMN was initially noted as disabled in some goal-oriented tasks and is sometimes referred to as a negative-task network, it may be active in other objective-oriented tasks, such as social work memory or autobiographical tasks. DMN is not correlated with other brain networks such as attention networks.

Studies on DMN have shown disturbances in the DMN of people with Alzheimer's disease and Autism Spectrum Disorder.

The value of neuroimaging for the diagnosis of bvAD

"This is the first study focused on bvAD to show such a variety of neuroimaging features," Singleton said. "This suggests that FDG-PET is more accurate in differentiating these diseases than MRI."

In a previous structural MRI study in 2015, Ossenkoppele and colleagues expected to find frontal cortical atrophy in people with bvAD, but were puzzled to find none.

Singleton and his colleagues examined the 150-person MRI and FDG-PET scans recruited at the University of California, San Francisco, and the University of Berkeley. BvAD was diagnosed in 29 patients, 28 in patients with typical Alzheimer's disease, 28 in patients with DVBt and 65 in cognitively normal subjects.

How does a TEP-FDG work?

Positron emission tomography (PET) scanners detect photons of light energy and construct three-dimensional images from the photons they receive. Scientists can use this ability to detect photons for medical diagnostic purposes if they know where these photons come from and what they represent.

The cells of the human body use glucose, a sugar, as the main source of energy to trigger all reactions and growth. FDG is a glucose molecule to which is attached a radioactive fluorine atom. It is radioactive, but it is not powerful enough to pose a significant risk to health.

When the FDG decomposes, it emits a particle called positron, which then divides into two photons. These are the photons produced by the FDG that the PET scanner detects. As FDG collects in highly active cells such as tumors, most photons come from these regions.

enter image description here Author Jens Maus http://jens-maus.de/

Metabolism and Alzheimer's

On PET-FDG scans, Singleton and colleagues found a pattern in patients with bvAD that was largely consistent with patients with typical Alzheimer's disease: hypometabolism in the posterior cingulate cortex, precuneus, and temporoparietal lateral. In addition, patients with bvAD had subtle metabolic deficits in fronto-insular areas, including the right lateral frontal lobe and bilateral insula, which did not appear in typical Alzheimer's disease (see image below). -above). This earlier pattern was more similar to that observed in sweeping examinations of patients with bvFTD.

The researchers also measured the uptake of FDG through the brain networks to look for changes in metabolic connectivity. Deficiency in the posterior default network (DMN) was lower in patients with bvAD and typical Alzheimer's disease than in controls, suggesting that these areas were affected in both types of AD. However, less absorption at the previous DMN distinguished bvAD from typical Alzheimer's disease and corresponded to the trend seen in bvFTD.

The researchers found no difference in terms of subcortical atrophy or white matter lesion between typical and bvAD.

These data suggest that common metabolic and connectivity deficits are at the basis of the behavioral phenotype shared by patients with bvAD and bvFTD.


This book traces the main achievements of ALS research over the last 30 years. He presents the drugs under clinical trial as well as ongoing research on future treatments likely within a few years, to stop the disease and provide complete treatment in a decade or two.

A new kind of cancer vaccine

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Immunotherapy on demand

Our frequent readers know that this site contains a peptide generator for designing simple, inexpensive and personalized cancer vaccines. Scientists believe that it is possible to use a system on the same principle, but much more effective.

Checkpoint inhibitors are not effective for many patients

Control point inhibitor immunotherapies are revolutionizing the treatment of cancer. However, even in the most sensitive cancers, a substantial proportion (50-80%) of patients have a low to no positive response. A surprising finding in the analysis of these patients was that one of the best correlates of response was the total number of neo-antigens in the tumor.

Basics of the new proposal

When information is transferred from DNA to RNA in cancer cells, errors occur frequently, resulting in the production of proteins that can be recognized by the immune system. Scientists at the Biodesign Institute at Arizona State University say these proteins, known as cancer-specific antigens, are important because they can be used to design vaccines that can treat or prevent tumor progression.

enter image description here

The common point of all cancer tumor mutations is the production of neo-antigens, or small fragments of proteins called peptides, formed inside a cancer cell, which the host's immune system had not yet never seen. These aberrant peptides, present only in cancer cells, can boost the immune system through a vaccine. They propose that mis-splicing and RNA transcription errors, particularly INDELs of MS in coding regions, in cancer cells could also be a source of neo-antigens.

These errors made by cancer cells can be used to develop a vaccine against some cancers

"In a cancer cell, it turns out that all levels of information transfer from DNA to RNA to protein become more prone to errors," said Johnston. "We proposed that these errors in cancer cells could also be the source of a cancer vaccine."

A "frame shift" or "splicing" error occurs when the DNA information of a gene is poorly processed during the fabrication of RNA, in a basic cellular process called transcription and splicing RNA.

For the most part, these alterations can be managed and cleaned by the cell, without ever being exposed to the immune system. As the cancer progresses, due to the increased number of errors, protein waste accumulates more rapidly, submerging the cell and aberrant proteins are exposed and recognized by the immune cell.

"These are overwhelming the quality control systems of a cell, generating errors in the RNA and proteins released by the cancer cell, which the immune system can respond to," said Johnston.

A new tool

To discover neo-antigens in tumors, Johnston's team has developed a new type of chip. They made fleas with the 200,000 possible neo-antigens for five common cancers, allowing them to simply search for antibodies present in the blood collected by patients. This is much simpler than the current practice of obtaining and sequencing tumor DNA, a starting point for the "personal cancer vaccines" that many companies are currently pursuing.

This set makes it possible to detect all possible predicted frame shift peptides that any tumor cell could potentially produce. They customized this chip, which contained nearly 400,000 peptides, and analyzed them with blood samples from cancer patients (and healthy control samples) to look for the peptides with the most reactive antibodies.

The basic idea is to make a vaccine containing multiple (up to 100) abnormal peptides.

Interest of this new type of immunotherapy

"Personal vaccines against cancer are complicated and expensive," said Johnston. "In addition, only about 40% of tumors have enough mutations in the DNA to make a vaccine. We have found that even cold tumors at the DNA level make many errors in the DNA. RNA: The peptides we generate are much more immunogenic than the point mutations used in personal cancer vaccines. More importantly, we can make standard vaccines for much cheaper therapeutic or even preventive vaccines. "

A vaccine that helps fight the development of resistance

It should be difficult for tumor cells to move away from the vaccine because these FSs are variants and not inherited mutations. In particular, if the FS antigen were produced in the RNA of an essential gene, the tumor cells would restrict the presentation of the MHC or create an immunosuppressive environment to evade an immune response.

In summary, scientists have discovered another class of neo-antigens that could be useful for developing different types of cancer vaccines. They have also created a matrix format for directly detecting immune responses to these tumor antigens.

What will happen to these works

Too often university laboratories stop their research when they can file a patent, in the very uncertain hope, that a large company will offer a golden bridge to buy that patent. This hope is often disappointed, simply because the patents resulting from academic research are not reproducible, but also because they do not respond to a large number of medical and regulatory issues. It is normally the role of biotech to solve these difficulties to make a process attractive for large companies. Our scientists are much more adept. They recently launched a large clinical trial of a pan-cancer prophylactic dog dog cancer vaccine funded by the Open Philanthropy Project. If that succeeds, Johnston is eager to move on to the first human clinical trials.

Regarding this web site, we could possibly design a peptide generator based on this principle. Please do not hesitate to contact us. "contact at padiracinnovation dot org"

Extracellular mitochondria and their impact on neurons

Mitochondria are frequently exchanged between cells and must change their shape accordingly to suit their environment. "Most scientists believe that mitochondria outside cells must have come from dead or dying cells," said Mochly-Rosen, who has just published an article in Nature Neuroscience. "But we found a lot of highly effective mitochondria in the culture broth, as well as some that were damaged, and the glial cells that release them seem very alive."

As recently discovered, even healthy cells regularly release mitochondria into their immediate environment.

An enzyme that destroys mitochondria

An enzyme called Drp1 that facilitates mitochondrial fission can become overactive because aggregates of neurotoxic proteins such as those associated with Alzheimer's, Parkinson's or Huntington's disease, or amyotrophic lateral sclerosis.

A fragment of protein that specifically blocks mitochondrial fission

About seven years ago, the Mochly-Rosen team designed a protein fragment, called the P110 peptide, that specifically blocks Drp1-induced mitochondrial fission when it occurs at an excessive rate, as it is the case when a cell is damaged.

Mitochondria and immune system

The relationship between mitochondria and eukaryotes has been critical to the success of metazoan life on Earth. Cellular colonization by ancestral α-proteobacteria more than a billion years ago provides benefits in terms of energy production and oxygen utilization. However, host cells needed to recognize and protect their increasingly essential endosymbioli while simultaneously identifying and repelling phylogenetically related pathogenic bacterial invaders. As a result, mitochondria have become immunologically preferred.

Nevertheless, misidentification of extracellular mitochondrial DNA, damaged mitochondria, or other damage-related molecular structures (DAMP) as a bacterium can trigger innate (sterile) immune mechanisms that in turn contribute to mitochondrial dysfunction. the spread of pathology in acute and chronic inflammatory diseases.

Loss of the immune privileged state is correlated with mitochondria damaged by microglia

Their results showed that the loss of the immune privileged state of extracellular mitochondria was correlated with an increased release of mitochondria damaged by microglia, and that the extracellular mitochondria damaged directly contributed to the spread of the disease by acting as the innate immune response by targeting adjacent astrocytes. and neurons.

An increase in Drp1 - Fis1 - mediated mitochondrial fission in activated microglia triggers the formation of fragmented and damaged mitochondria that are released from these cells, thereby inducing an innate immune response.

Fragmented mitochondria are biomarkers of neurodegeneration

Clinical and experimental studies have identified fragmented mitochondria in the biofluids of patients with subarachnoid hemorrhage and stroke patients, suggesting that their presence in the extracellular space is a biomarker of neurodegeneration and neurodegeneration. the severity of the disease. Their data showed a causal role of dysfunctional extracellular mitochondria in the propagation of neurodegenerative signals from microglia. Innate immune responses in neurodegenerative diseases begin early in the pathogenesis of these diseases and are associated with minimal, if any, infiltration of immune cells derived from blood in the brain. Resident brain cells, microglia and astrocytes, trigger this sterile immune response, contributing to neuronal dysfunction and degeneration.

P110 peptide reduces the release of damaged mitochondria from microglia

The authors have previously reported that neurons harbor neurotoxic proteins. Their data showed that the Drp1-Fis1 inhibitory peptide P110 reduces mitochondrial fission and subsequent release of damaged mitochondria from microglia, thereby inhibiting astrocyte activation and protecting neurons from innate immune attacks.

A vicious circle leads to neurodegeneration

Their data suggest instead that a relay of glie-neuron-to-glia signaling plays an important role in neurodegeneration. By fueling the vicious circle, neurotoxic protein-induced neuronal death generates additional cellular debris and debris (DAMP), as well as dysfunctional mitochondria released by microglia expressing neurotoxic proteins, exacerbate astrocyte activation. and chronic pathogenic inflammation.

Thus, neuronal cell death and the final phenotype of the disease occur via the activation of the innate immune response as well as via the direct effects of neurotoxic protein-induced cell death.

Activation of the innate immune response and neuronal protein-induced neuronal cell death in neurodegenerative disease models are both dependent on excessive Drp1-Fis1-induced mitochondrial fragmentation.

The minimal amount of damaged mitochondria required for the propagation of neuronal cell death is also unknown, and the transfer of functional mitochondria between microglia and astrocytes and between glia and neurons plays a role in physiological conditions. However, researchers know that extracellular mitochondria are essential for mediating this pathological pathology from cell to cell.

The ratio of damaged mitochondria to functional mitochondria in the extracellular medium determines the fate of neurons. Although damaged extracellular mitochondria are deleterious, functional mitochondrial transfer is protective, as previously demonstrated, for example in a murine model of acute lung injury and in a stroke model. The question of whether extracellular mitochondria damaged enter the neurons, as suggested for functional mitochondria in a previous study, has not yet been determined.

It is not the amount of extracellular mitochondria but rather the ratio of damaged mitochondria to functional mitochondria in the extracellular environment that governs the outcome of neurons and is determined by the extent of pathological fission in the microglia donor.

A slow path to developing a drug

Their data suggest that selective inhibition of pathological mitochondrial fission in microglia (mediated by Drp1 - Fis1) without affecting mitochondrial physiologic fission reduces the propagation of neuronal injury by two mechanisms

First, P110 reduced activation of the innate immune response in microglia and astrocytes and cytokine-induced neuronal cell death induced by extracellular and dysfunctional mitochondria.

Second, the inhibition of pathological mitochondrial fission by P110 in donor microglia contributed to neuronal cell survival by increasing the ratio of healthy mitochondria to damaged ones released by donor cells, thereby protecting neurons.

Suppression of DrP1 - Fis1 mediated mitochondrial fission is an easily translatable approach to interrupting this pathogenic microglia-to-astrocyte-to-neuron mitochondrial pathology, and promoting the transfer of healthy mitochondria to neurons.

However, they consider that any means of normalizing the balance between healthy and damaged mitochondria within the neuronal environment, for example by removing damaged and fragmented mitochondria with specific antibodies or by introducing healthy mitochondria, could also provide neuronal protection in neurodegenerative diseases.

Article from Nature Neuroscience: Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Who we are

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Padirac Innovation is a ** non-profit organization ** created in France in the middle of 2014. It aims to produce technological tools for human needs.

Here are its activities so far:

From 2014 to 2016, Padirac Innovation solved the following Innocentive problems:

  • Inventing a tool to deactivate abandoned chemical warfare,

  • Finding a drug for eczema that is currently without valid IP,

  • Helping Cleveland Clinic with new strategies to mitigate the adaptation of prostate cancer cells to new drugs.

In 2017, Padirac Innovation developed an early heart failure detector

This heart failure detector uses artificial intelligence to detect S4 sounds with a mini ultrasound Doppler.

From 2018, Padirac Innovation has worked specifically on cancer and ALS

  • In the first half of 2018, Padirac Innovation developed reliable information in French on health care related to cancer.
  • In the second half of 2018, Padirac Innovation designed several achievements related to ALS.

In 2019, Padirac Innovation is writing a book about ALS research

English version

French version

Study of Edaravone in ALS Korean patients.

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Purpose of this study

Edaravone was approved as a therapeutic drug against ALS in June 2015 in Japan and by the Korean Ministry of Food and Drug Safety in December 2015.

In this observational study, on ALS patients in the Korean population, patients treated with edaravone showed modest results on ALSFRS-R and lung function tests. Several previous studies on edaravone also reported quite low results in the treatment of ALS.

Results of this new study on Edaravone

The phase 3 clinical trial on edaravone showed an average decrease in ALSFRS-R of 5.01 points in 6 months in the treated group, and an average decrease of 7.50 points in 6 months in the control group.

The patients involved in this study showed an average decrease of 5.75 point.

The initial characteristics of ALS patients included in this study had an average ALSFRS-R of 34.25 and an average CVF of 75%, reflecting a more advanced stage of ALS patients in this new study compared to patients in the recent trial. phase 3 clinical trial.

It should be noted that a recent study of advanced ALS patients with a FVC of less than 60% showed no benefit of edaravone, reflecting the importance of early intervention in the treatment of ALS patients. The study in Korean patients also showed some efficacy in ALS patients with a mean CVF score of 75%.

In the present study, the results also indicate that the reduction is not limited to a specific area, but also relates to different areas of ALSFRS-R.

Castillo-Viguera et al. have suggested that removal of more than 20% of ALSFRS-R is clinically significant; The phase 3 clinical trial on edaravone had shown a 33% decrease in progression, but the present study showed only a slower progression of 23% after 6 months.

Adverse effects of Edaravone

Edaravone is known to cause frequent side effects, in up to 84% of patients. The most common side effects are bruising, constipation, contact dermatitis, dysphagia, eczema and inflammation of the upper respiratory tract (in order of decreasing frequency); 16% of patients experienced serious adverse events. In the present study, two patients presented with eczema and pruritus, which were well tolerated with oral antihistamine and steroidal therapy. Transient leukopenia should also be noted in a patient who has recovered after a few days of initial treatment. No deaths were encountered during the follow-up period.

The limitations of the present study are as follows. The study was observational, with no control group for comparison. The small number of patients recruited must be taken into account in the evaluation of the results.


This is a study of Korean patients on the open-label study of edaravone in patients with ALS. The treatment was well tolerated without significant adverse events. Consistent with previous studies in Japan, the United States and Europe, the present study shows that the treatment was well tolerated and showed only a slight improvement at a later stage of ALS.

The study is available here: https://doi.org/10.1007/s10072-019-04055-3


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

The majority of patients still do not respond to immune checkpoint treatments.

This type of treatment had been presented as revolutionary a few years ago. Unfortunately, medical research has accustomed us to these shattering announcements that never materialize. A subtype of macrophages, a form of immune cells with anti-inflammatory properties, protects rather than destroys cancer cells. Instead of directly attacking cancer cells, a new immunotherapy technique targets and removes this subtype of macrophages, after which the immune system begins to reduce cancer.

Tumor-associated macrophages

Tumor-associated macrophages are the most abundant immune cells present in solid tumors, and the fact that they contribute significantly to tumor progression is well documented.

In addition to their trophic functions favoring angiogenesis, invasion, and metastasis, tumor-associated macrophages may inhibit proliferation and activation of T-cells by various mechanisms.

Bad clinical results, but not everywhere

The important functions of macrophages in relation to tumor progression have led to a substantial interest in the development of new therapeutic strategies for targeting tumor-associated macrophages.

However, despite a strong correlation between tumor-associated macrophage accumulation and poor clinical trial results, in some cases the accumulation of macrophage subsets associated with specific tumors may be associated with a good prognosis.

An example is the frequency of HLA-DR + tumor-associated macrophages, which has been associated with beneficial effects in several studies (de Vos van Steenwijk et al., 2013, Ino et al., 2013), perhaps reflecting the role of macrophages in orchestrating protective immune responses (Mantovani and Allavena, 2015).

In fact, recent studies using a coupled monocell analysis by mass cytometry and RNA sequencing have revealed an unprecedented level of diversity within the tumor-associated macrophage compartment in patients with lung adenocarcinoma and cell carcinoma kidney (Chevrier et al., 2017; Lavin et al., 2017). In the case of renal cell carcinoma, 17 different tumors-associated macrophage phenotypes have been documented (Chevrier et al., 2017).

Diversity of tumor-associated macrophage subsets

Researchers still lack basic knowledge about the functions of different subsets of tumor-associated macrophages and their respective contributions to tumor progression.

However, it is tempting to think that selective targeting of tumor-associated macrophage subsets with protumoral functions, while preserving the immune functions of other tumor-associated macrophage subsets, could offer significant clinical benefits .

CD163 protein as a marker of bad proostic

The expression of CD163 by tumor-associated macrophages has been shown to be a particularly potent indicator of poor prognosis in several human cancers (Komohara et al., 2014), including melanoma (Jensen et al., 2009; Bronkhorst et al. al., 2011; Lee). et al., 2018).

CD163 is a macrophage and monocyte-specific transmembrane protein that acts as a receptor for haptoglobin-hemoglobin complexes formed during intravascular hemolysis (Kristiansen et al., 2001). Hemoglobin is contained in red blood cells or red blood cells. In case of destruction of the latter (physiologically or not), the hemoglobin-haptoglobin complex is removed from the plasma mainly at the level of the spleen.

CD163 expression is induced by tumor-promoting cytokines such as IL-6 and IL-10, whereas inflammatory stimuli, including LPS, TNFα, and IFNγ, result in rapid expression regulation. and removal of the CD163 membrane via proteolytic excretion (Etzerodt et al., 2010; Etzerodt and Moestrup, 2013).

This, combined with the generation of heme anti-inflammatory metabolites from hemoglobin scavenging, has led to the association of CD163 + macrophages with anti-inflammatory functions (Etzerodt and Moestrup, 2013).

Caution is needed

Indeed, the link between CD163 accumulation and tumor-associated macrophages and tumor progression is based exclusively on correlations with clinical evolution, and experimental evidence of specific promotion functions. the tumor are still missing.

Moreover, the recent development of immune check point inhibitors (immune control point), such as anti-PD-1, has had a huge impact on the treatment of cancer, particularly in malignant melanoma (Robert and al., 2015; Ugurel et al., 2017). The blocking of PD-1 / PD-L1 signaling has resulted in unprecedented tumor regression rates (Tumeh et al., 2014), but only for a small number of patients.

New therapeutic strategies

Therefore, new therapeutic strategies to enhance antitumor immunity, to overcome immune checkpoint resistance or to improve serious adverse side effects, are absolutely necessary.

Researchers conducted extensive characterization of tumor-associated macrophage subsets in a clinically relevant mouse model of melanoma resistant to anti-PD-1 treatment.

The researchers show that the specific targeting of a minor subset of macrophages associated with tumors expressing CD163 is sufficient to induce tumor regression in this model.

It is important to note that the specific macrophage depletion associated with CD163 + tumors results in increased recruitment of effector T cells and CCR2-dependent inflammatory monocytes, both of which contribute to tumor regression.

These studies are the first to demonstrate the selective targeting of macrophages associated with tumors and CD163 and their specific contribution to tumor progression.

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