Neurodegenerative diseases are often sometimes to a virus, in particular HERV-K, but this has never been demonstrated convincingly.

Hepatitis E virus (HEV) infections are not limited to the liver but can also affect other organs. Several neurodegenerative diseases including Guillain-Barré syndrome, neuralgic amyotrophy, meningitis, have been observed in the context of hepatitis E. Additionally, HEV infection has been observed with other neurological diseases, such as encephalitis, myelitis, and Bell's palsy. Patients may have normal liver function tests, which can often mislead doctors into inferring that there is no HEV infection.

Case-control studies are a type of epidemiological study. They have often been used in the study of rare diseases where little is known about the association between the risk factor and the disease of interest.

Case-control studies are used to identify factors that may contribute to a disease by comparing subjects who have that disease (the “cases”) with patients who do not have the disease but are otherwise similar (the “controls”).

In this case-control study, scientists from Spain assessed the association between serum antibodies against the hepatitis E virus and neurodegenerative disorders of the central nervous system in older people with dementia.

The presence of anti-HEV antibodies was related to a higher adjusted odds ratio of having neurodegenerative disorders by neuropathological diagnosis and clinical/neuropathological diagnosis.

Furthermore, serum anti-HEV antibodies were directly linked to neuropathological injury and a higher likelihood of having Alzheimer-like pathology.

The scientists conclude their article by assuming that the presence of anti-HEV antibodies was indeed linked to a higher risk of neurodegenerative disorders and neuropathological lesions in the elderly.

However, the reader should exercise caution. Case-control studies are observational in nature and do not provide the same level of information as randomized controlled trials. The results can be distorted by other factors, sometimes significantly.

Aging is an important risk factor for neurodegenerative disorders (neurodegenerative disorders), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD ).

Protein synthesis has historically been described as decreasing with age, although not all studies agree and often point to high organ and tissue variability. Protein degradation is also commonly described as compromised in aging

Analysis of brain protein levels in the physiologically aged brain, however, showed only minor changes in protein abundance in the older adult brain compared to the young adult brain. However, a recent theory indicates that the alterations observed in neurodegenerative disorders could be linked to the minimization of proteomic costs, reflecting a new prioritization of bioenergetic costs, which would preserve the most "expensive" proteins in energy from the aged brain while replacing more easily metabolically less expensive proteins.

To test this theory, it is interesting to study protein turnover, which regulates the balance between protein synthesis and degradation, because it could be particularly affected by aging and could lead to changes prelude to neuropathology. The turnover of proteins begins with their destruction, the catabolism of proteins is a key function of the digestive process. The amino acids resulting from these proteins thus degraded can be transformed into fuel for the Krebs cycle/citric acid (TCA).

Researchers led by Anja Schneider of the German Center for Neurodegenerative Diseases in Bonn and Eugenio Fornasiero of the University Medical Center Göttingen, both in Germany, measured the half-lives of more than 3,500 proteins in mouse brain. They found an average increase of 20 percent with age.

For Alzheimer's disease, these life-extending proteins included:

• the group of Tau proteins (MAPT)
• ADAM10 which is correlated with the appearance of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer's disease.
• DBN1 A decrease in the amount of this protein in the brain has been implicated as a possible contributing factor in the pathogenesis of memory impairment in Alzheimer's disease.
• CTSDs which are implicated in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer's disease.

For Parkinson's disease, they included:

• Alpha-synuclein, a protein which in humans is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and the subsequent release of neurotransmitters. It is abundant in the brain, while smaller amounts are found in the heart, muscle, and other tissues. In the brain, alpha-synuclein is found primarily in the axon terminals of presynaptic neurons.

  Alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. These disorders are known as synucleinopathies.

• PARK7, Under oxidative conditions, the deglycase protein DJ-1 inhibits the aggregation of α-synuclein via its chaperone activity, thus functioning as a redox-sensitive chaperone and as an oxidative stress sensor. The functional protein DJ-1 has been shown to bind to metals and protect against metal-induced cytotoxicity of copper and mercury. Defects in this gene cause early-onset autosomal recessive Parkinson's disease

For ALS, they included:

• TUBA4A, The alpha-4A chain of tubulin is a protein which in humans is encoded by the TUBA4A gene. This gene has only rarely been associated with ALS. Overall, ALS-related genes can be categorized into four groups based on the cellular pathways in which they are involved: (1) protein homeostasis; (2) homeostasis and RNA trafficking; (3) cytoskeletal dynamics; and (4) mitochondrial function.

  The reason TUBA4A might be associated with ALS is that motor neurons and skeletal muscle cells are known to be the largest cells in the human body. The significant length of these cells makes them highly dependent on the correct architecture of the cytoskeleton, the integrity of which is essential for the axonal transport necessary to maintain the integrity of synapses. Several mutations in the tubulin beta-4A (TUBA4A) gene destabilize microtubules by impairing repolymerization, likely contributing to axonal degeneration in MN.

• SOD1, whose protective role against oxidative stress has been well studied, but whose mutations were previously only associated with 25% cases of familial ALS.

Conclusion The authors of this article observed a previously unknown alteration in proteostasis that is correlated with parsimonious protein turnover with high biosynthetic costs, revealing a global metabolic adaptation that preludes neurodegeneration.

However, nothing in this study explains how malformed, poorly localized proteins might appear. This study only shows a correlation between the half-life of proteins and certain neurodegenerative diseases.

Their results suggest that future therapeutic paradigms, aimed at addressing these metabolic adaptations, may be able to delay the onset of neurodegenerative disorders.

Among these we could mention certain factors related to metabolism which determine the half-life of proteins such as pH and temperature. It is well known that aging cells have an increasing pH: They become basic. when the daughter cells come from an aging mother cell, the daughter's age is "reset". A parent cell becomes less acidic as the parent cell ages. Daughter cells, on the other hand, have very acidic vacuoles.

Introduction The ketogenic diet has been used since the beginning of the 20th century to reduce the incidence of epileptic seizures, and over time its application to other diseases has been studied.

This diet is characterized by a high content of unsaturated fatty acids, few carbohydrates and a normal protein content. While in a traditional diet there is about 55% of the energy value in the form of carbohydrates, about 30% fat and 15% protein, these proportions in the classic ketogenic diet are 8% for carbohydrates, 90% for lipids and about 7% for proteins. The most common form of the ketogenic diet includes mostly long-chain fatty acids.

The drastic changes induced by the ketogenic diet in eating habits are difficult to maintain in a long-term perspective. This is because high volumes of high fat components in the diet (cheeses, eggs, butter, oils, meat, etc.) can lead to nausea, vomiting, constipation and loss of appetite.

Adverse effects of the ketogenic diet The ketogenic diet, as a high-fat, low-carb diet, is associated with some insufficiency in the energy value of food portions and leads to metabolic effects that ultimately reduce body weight. People suffering from neurodegenerative diseases are at high risk of malnutrition and therefore this type of diet seems a priori to be contraindicated for them. People with neurodegenerative diseases suffer from sarcopenia which is often fatal.

According to current recommendations, people at risk should consume 1.0 to 1.2 g of protein/kg per day, or even more if they are physically active. The ketogenic diet, particularly when the energy value of the diet decreases, may therefore lead to a protein intake that is too low, although its contribution to the energy value of the diet may be normal or even higher than recommended. Such a situation can lead to the catabolism of structural proteins (especially in the muscles).

In individuals with insulin resistance, diabetic acidosis can be identified, which is a disease state with ketone body concentrations above 25 mmol/L, resulting from insulin deficiency with a simultaneous increase in glucose concentration ( > 300 mg/dL) and a decrease in blood concentration. pH (pH < 7.3), which can cause death.

Ketogenic diet and Alzheimer's disease It is not easy to formulate a ketogenic diet, in fact saturated fatty acids are present everywhere in large quantities, particularly in foods associated with pleasure, desserts, dairy products, chocolates. Eating a single meal high in saturated fat is enough to reduce our ability to concentrate, much more than if it is a meal high in unsaturated fat. Epidemiological studies show that a diet rich in saturated fatty acids increases the risk of Alzheimer's disease.

Studies conducted on an animal model of Alzheimer's disease, however, indicate a possible beneficial effect of the ketogenic diet for this medical condition.

Reger et al. concluded that oral administration of medium-chain triglycerides elevates plasma levels of ketone bodies and may improve cognitive functioning in older adults with memory impairment.

Henderson et al. administered medium-chain triglycerides to subjects with mild and moderate Alzheimer's disease. Administration of this type of fat resulted in improved cognitive functioning. It should be noted, however, that no effect of this type was observed in subjects carrying the APOEε4 genotype.

Ota et al. administered medium-chain triglycerides to 20 patients with mild to moderate Alzheimer's disease. After 8 weeks, patients showed significant improvement in their immediate and delayed logical memory tests compared to their baseline score. At 12 weeks, they showed significant improvement in the Numerical Symbol Coding Test and Logical Immediate Memory tests compared to baseline.

In the Ketogenic Diet Retention and Feasibility Trial, 15 patients with Alzheimer's disease maintained a ketogenic diet supplemented with medium-chain triglycerides (approximately 70% of energy as fat, including triglycerides at medium chain; 20% of energy as protein; and less than 10% of energy as carbohydrate). They have observed that when fully achieved ketosis, the mean score of the cognitive subscale of the Alzheimer's Disease Rating Scale improved significantly during the diet but returned to baseline at its termination.

Krikorian et al. applied a high carbohydrate diet to 23 subjects with mild cognitive impairment. After 6 weeks of intervention, the authors observed an improvement in verbal memory performance in subjects on a low carbohydrate diet. The authors concluded that even short-term use of a low-carb diet could improve memory function in older adults at increased risk for Alzheimer's disease. Although the observed effect may be partly attributable to the correction of hyperinsulinemia, other mechanisms associated with ketosis, such as reduced inflammation and improved energy metabolism, may also have contributed to the improved neurocognitive functioning.

Adapted from "Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease)" Dariusz Włodarek doi: 10.3390/nu11010169

Introduction Le régime cétogène a été utilisé dès le début du XX siècle pour réduire l'incidence des crises d'épilepsie et, au fil du temps, son application à d'autres maladies a été étudiée,.

Ce régime se caractérise par une teneur élevée en acides gras non saturées, peu de glucides et une teneur normale en protéines. Alors que dans un régime traditionnel il y a environ 55% de la valeur énergétique sous forme de glucides, environ 30% de lipides et 15% de protéines, ces proportions dans le régime cétogène classique sont de 8% pour les glucides, 90% pour les lipides et environ 7% pour les protéines. La forme de régime cétogène la plus fréquente comprend principalement des acides gras à longue chaîne.

Les changements drastiques induits par le régime cétogène dans les habitudes alimentaires, sont difficiles à maintenir dans une perspective à long terme. En effet des volumes élevés de composants riches en matières grasses dans l'alimentation (fromages, œufs, beurre, huiles, viande, etc.) peuvent entraîner des nausées, des vomissements, de la constipation et une perte d'appétit.

Effets indésirables du régime cétogène Le régime cétogène, en tant que régime riche en graisses et pauvre en glucides, est associé à une certaine insuffisance de la valeur énergétique des portions alimentaires et conduit à des effets métaboliques qui finissent par réduire le poids corporel. Les personnes souffrant de maladies neurodégénératives sont à haut risque de malnutrition et donc ce type de régime semble à priori être contre indiqué pour elles. Les personnes atteintes de maladies neurodégénératives souffrent d’une sarcopénie qui est souvent fatale.

Selon les recommandations actuelles, les personnes à risque devraient consommer 1,0 à 1,2 g de protéines/kg par jour, voire plus si elles sont physiquement actives. Le régime cétogène, en particulier lorsque la valeur énergétique du régime diminue, peut donc conduire à un apport général en protéines trop faible, bien que sa contribution à la valeur énergétique du régime puisse être normale ou même supérieure à celle recommandée. Une telle situation peut conduire au catabolisme des protéines structurelles (en particulier dans les muscles).

Chez les personnes souffrant d'insulinorésistance, une acidose diabétique peut être identifiée, qui est un état pathologique avec des concentrations de corps cétoniques supérieures à 25 mmol/L, résultant d'un déficit en insuline avec une augmentation simultanée de la concentration en glucose (> 300 mg/dL) et une diminution de la concentration sanguine. pH (pH < 7,3), pouvant entraîner la mort.

Régime cétogène et maladie d'Alzheimer Il n’est pas aisé de formuler un régime cétogène, en effet les acides gras saturés sont partout présents en grande quantité, particulièrement dans les nourritures associées au plaisir, desserts, produits lactés, chocolats. Prendre un seul repas riche en graisses saturées suffit à diminuer notre capacité de concentration, nettement plus que s'il s'agit d'un repas en graisses non-saturées. Les études épidémiologiques démontrent qu'une alimentation riche en acides gras saturés augmente le risque de maladie d'Alzheimer.

Des études menées sur un modèle animal de la maladie d'Alzheimer indiquent cependant un effet bénéfique possible du régime cétogène pour cette condition médicale.

Réger et al. ont conclu que l'administration orale de triglycérides à chaîne moyenne entraînait une élévation des taux plasmatiques de corps cétoniques et qu'elle pouvait améliorer le fonctionnement cognitif chez les personnes âgées souffrant de troubles de la mémoire.

Henderson et al. ont administrés des triglycérides à chaîne moyenne à des sujets atteints de la maladie d'Alzheimer légère et modérée. L'administration de ce type de graisse la entraîné une amélioration du fonctionnement cognitif. Il convient cependant de noter qu'aucun effet de ce type n'a été observé chez les sujets porteurs du génotype APOEε4.

Ota et al. administré des triglycérides à chaîne moyenne à 20 patients atteints de la maladie d'Alzheimer légère à modérée. Après 8 semaines, les patients ont montré une amélioration significative de leurs tests de mémoire logique immédiate et différée par rapport à leur score de base. À 12 semaines, ils ont montré une amélioration significative du test de codage des symboles numériques et des tests de mémoire logique immédiate par rapport à la ligne de base.

Dans l'étude Ketogenic Diet Retention and Feasibility Trial, 15 patients atteints de la maladie d'Alzheimer ont maintenu un régime cétogène complété par des triglycérides à chaîne moyenne (environ 70 % de l'énergie sous forme de lipides, y compris les triglycérides à chaîne moyenne ; 20 % de l'énergie sous forme de protéines ; et moins de 10 % de l'énergie sous forme de glucides). Ils ont observé qu'en cas de cétose complètement atteinte, la moyenne du score de la sous-échelle cognitive de l'échelle d'évaluation de la maladie d'Alzheimer s'améliorait de manière significative pendant le régime mais revenait à son point de départ à sa cessation.

Krikorian et al. appliqué un régime riche en glucides chez 23 sujets présentant une déficience cognitive légère. Après 6 semaines d'intervention, les auteurs ont observé une amélioration des performances de la mémoire verbale chez les sujets sous régime pauvre en glucides. Les auteurs ont conclu que même l'utilisation à court terme d'un régime pauvre en glucides pourrait améliorer la fonction de mémoire chez les personnes âgées présentant un risque accru de maladie d'Alzheimer. Bien que l'effet observé puisse être attribuable en partie à la correction de l'hyperinsulinémie, d'autres mécanismes associés aux cétoses, tels que la réduction de l'inflammation et l'amélioration du métabolisme énergétique, peuvent également avoir contribué à l'amélioration du fonctionnement neurocognitif.

Adapté de "Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease)" Dariusz Włodarek doi: 10.3390/nu11010169

Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer's disease (AD), Parkinson's disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. The precise mechanism of extracellular aggregate transfer and induction of new aggregates is unclear.

Yet only a small fraction of released soluble or aggregated proteins are associated with extracellular vesicle, while the vast majority is freely secreted.

So there is an apparent paradox: If proteins aggregates are not usually found in extracellular vesicles, how could it be that they are causing aggregates?

The usual explanation is that extracellular vesicles are seeding protein aggregates, which might be a good enough explanation in extracellular medium. Yet in humans only Alzheimer disease has extracellular proteins aggregates but has also intracellular aggregates of Tau protein, for most other diseases, the protein aggregates are only intracellular.

Scientists from the German Center for Neurodegenerative Diseases Bonn (DZNE) and the German Centre for the Protection of Laboratory Animals (Bf3R), hypothesized that for one extracellular vesicle to penetrate in a foreign cell, it has to have ligands are present that bind to receptors on the cell surface and then cause the two membranes to fuse. https://www.nature.com/articles/s41467-021-25855-2

The researchers induced cells to produce viral proteins that mediate target cell binding and membrane fusion. Two proteins were chosen as prime examples: SARS-CoV-2 spike protein S, which stems from the virus causing COVID-19, and vesicular stomatitis virus glycoprotein VSV-G, which occurs in a pathogen that is clinically similar to the Foot-and-mouth disease but from a different family.

Moreover, cells expressing receptors for these viral proteins, and with poor aggregate-inducing activity in recipients were chosen.

They found that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase extracellular aggregates of misfolded proteins in infected cells.

• Expression of viral glycoprotein VSV-G drastically increases cell-to-cell spreading of cytosolic prions
• Enhanced extracellular transmission of Tau aggregation upon VSV-G expression
• VSV-G extracellular vesicle efficiently transmit scrapie prions to recipient cells

There is little about intracellular aggregates in this article, as the researchers' focus is obviously on neurodegenerative animal diseases.

Misfolded proteins are located in the cytosol, proteins fold for a reason, it is the endoplamic reticulum (ER) which folds them. There is no mention of the ER in this article. Yet it looks like that a protein which cause membranes to fuse would destroy organelles like the ER.

The German scientists worked on Tau protein and PrP protein, but there is no mention of TDP-43 and synuclein. Probably because those two proteins are found in (human) intracellular aggregates.

In another recent article, another team found that VSV-G caused marked alterations in cell's secretory trafficking, with VSV-G accumulating mainly in the Golgi complex . https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8059059/ The Golgi apparatus is the dispatch station of protein received from the endoplasmic reticulum (ER). ER is the place where linear proteins just produced by the ribosomes are correctly folded.

So a protein disturbing the ER or Golgi apparatus is certainly creating proteopathies such as the one seen in human neurodegenerescence.

Yet that does not prove that VSV-G is the cause of neurodegenerescence. There is nearly nearly no publications associating VSV-G and neurodegenerescence.

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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.

I increasingly believe that the consistently negative results of clinical trials in most degenerative diseases are not because these diseases are difficult to understand, but because most of the scientists who contribute to them are molecular biologists and not doctors or system biology engineers.

*Detail from "Triumph of St. Thomas Aquinas over Averroes" by Benozzo Gozzoli (1420–97)*

Molecular biologists do not care for anatomy of physiology, even worse, they treat the 200 different types of cells in the body as mostly similar. Even if most of neurodegenerative diseases involve anatomical structures that are found only in primates, their animal models are non-primate, and indeed they are astonished that good clinical results in mice do not translate in human beings.

They do not even agree if ALS starts in the brain or in muscles ("dying forward" hypothesis versus "dying backward" hypothesis). Astonishingly several times they "proved" that each of their favorite hypothesis was true and that indeed the competing hypothesis was false.

For ALS alone they implicated more than 120 genes, even if the notion of gene (as a single DNA region which is uniquely implicated in coding a specific strand of RNA) is extremely vague. And they did this before finding that, what was thought as a non coding region (C9orf72) was implicated in ~50% of familial ALS cases. Now C9orf72 is called a gene, so everything is safe again.

Like medieval scholars who discussed how many angels could stand on the tip of a pin, they proposed thousands of small molecules as the causal mechanism for Alzheimer's, Parkinson's, or ALS. The profusion of proposals and the lack of discussion of competing proposals should surely question anyone with a rational mind?

And some authors have stated non-mainstream research proposals were blocked since decades.

This kind of scientist has lost credibility.

There are alternating views, notably by Heiko Braak who says that Parkinson and Alzheimer start with a pathogen invasion in guts and its subsequent progression into the brain. And he and his colleagues provided good evidence for that.

Braak is a medical doctor, but molecular biology scientists did not think much of his findings. Braak is cited only by 0.3% of articles on Parkinson disease.

For a better explanation of why trying to understand something by dissecting it in components and making experiments on isolated components does not help to comprehend how a system works, look at the famous article "Can a biologist fix a radio?"

So in my current view we call different neurodegenerative diseases with different names, but they are mostly the same disease. Whatever neurons are dying in the substantia nigra (Parkinson), primary motor cortex (ALS), or lobes (Alzheimer) it is mainly about neurons dying in the brain. And it is a problem that cannot be solved with molecular biology.

Un approvisionnement adéquat en sang est essentiel au fonctionnement normal du cerveau. D'un autre côté, les déficits du flux sanguin cérébral et le dysfonctionnement de la barrière hémato-encéphalique sont des signes précoces de troubles neurodégénératifs chez l'homme et les modèles animaux.

Un approvisionnement suffisant en sang des 86 milliards de neurones du cerveau humain, est obtenu grâce à un vaste réseau vasculaire bien régulé d'artères, d'artérioles, de capillaires, de veinules et de veines atteignant environ 600 km de longueur. L'activité neuronale déclenche une augmentation de l'approvisionnement régional en sang oxygéné en quelques millisecondes. C'est ce que l'on appelle la réponse hémodynamique ou le couplage reurovasculaire.

Deux nouvelles études décrivent les éléments de la physiologie neurovasculaire qui rendent cet exploit possible. L'un, publié dans Nature le 19 février 2020 et dirigé par Chenghua Gu à la Harvard Medical School, rapporte que les cellules endothéliales qui tapissent les artérioles arborent une myriade d'entrées, appelées cavéoles, qui contrôlent en quelque sorte la dilatation rapide des artérioles en réponse à la stimulation neuronale. L'autre, publié le 20 janvier dans Nature Communications et dirigé par Martin Lauritzen de l'Université de Copenhague, décrit des sphincters spécialisés qui contrôlent le flux sanguin des artérioles du cerveau vers ses vastes lits capillaires.

En plus de la maladie d'Alzheimer, le système vasculaire cérébral a été impliqué dans la pathogenèse de la démence frontotemporale, la maladie de Parkinson, la maladie de Huntington, la sclérose latérale amyotrophique (SLA), la sclérose en plaques et d'autres conditions neurodégénératives telles que le trouble neurocognitif induit par le VIH.

Les patients SLA développent également des déficits de perfusion dans le cortex fronto-pariétal.

Le modèle conventionnel postule que la réponse hémodynamique est médié par des facteurs vasodilatateurs dérivés des neurones qui détendent directement les cellules musculaires lisses artérielles. Pourtant, d'après des travaux récents, il semble que les cellules endothéliales cérébrales puissent également détecter l'activité neuronale. Peut-être alors que les signaux vasodilatateurs agissent d'abord sur les cellules endothéliales cérébrales avant d'être relayés aux cellules musculaires lisses artérielles.

Chow et al. explorent ce potentiel couplage neurovasculaire médiée par les cellules endothéliales cérébrales en adoptant une approche très élégante. Ils se sont concentré sur le cortex somatosensible de souris de laboratoire, où la stimulation des moustaches déclenche de manière fiable l'activité neurale, la dilatation des vaisseaux et le flux sanguin. Ils montrent que la détection classique d’oxyde nitrique dans les cellules musculaires lisses est insuffisante pour un couplage neurovasculaire complet.

Au lieu de cela, les cavéoles enrichies en cellules endothéliales cérébrales artériolaires sont également nécessaires pour un couplage efficace. À l'aide de divers modèles de souris spécifiques au type cellulaire et de gène global de knockout et de surexpression, ils confirment que les cavéoles dans les cellules endothéliales cérébrales – et non les cellules musculaires lisses artérielles - sont nécessaires pour le couplage neurovasculaire.

Ces découvertes inspirent des questions passionnantes pour comprendre la biologie du système vasculaire cérébral en matière de santé, de vieillissement et de maladie.

Quel est le mécanisme par lequel les cavéoles médient le couplage neurovasculaire? Quelles sont les molécules vasodilatatrices spécifiques? Existe-t-il des mécanismes pour engager préférentiellement les cavéoles cellules endothéliales cérébrales par rapport à la voie oxyde nitrique? Comment les changements documentés de l'expression des gènes cellules endothéliales cérébrales avec le vieillissement sont-ils liés au couplage neurovasculaire? Enfin, comment ce modèle évolue-t-il avec la maladie? Par exemple, l'accumulation vasculaire de β-amyloïde dans l'angiopathie amyloïde cérébrale a été corrélée à une perte de cellules musculaires lisses artérielles.

En bref, la présente étude donne un nouvel élan à l'étude de la complexité fascinante du système vasculaire cérébral et, espérons-le, ouvrira la voie à une meilleure compréhension de la façon dont cette structure dégénère avec l'âge et la maladie.

An adequate blood supply is essential for normal brain function. On the other hand, deficits in cerebral blood flow and dysfunction of the blood-brain barrier are early signs of neurodegenerative disorders in humans and animal models.

A sufficient supply of blood from the 86 billion neurons in the human brain is obtained through a large, well-regulated vascular network of arteries, arterioles, capillaries, venules and veins up to approximately 600 km (400 miles) in length. Neural activity triggers an increase in the regional supply of oxygenated blood within milliseconds. This is called either haemodynamic response or reurovascular coupling.

Two new studies describe the elements of neurovascular physiology that make this feat possible. One, published in Nature on February 19, 2020 and edited by Chenghua Gu at Harvard Medical School, reports that the endothelial cells lining the arterioles have a myriad of entries, called caveolae, which somehow control the rapid dilatation of the arterioles in response to neural stimulation. The other, published on January 20 in Nature Communications and directed by Martin Lauritzen of the University of Copenhagen, describes specialized sphincters that control blood flow from arterioles from the brain into its large capillary beds.

In addition to Alzheimer's disease, the cerebrovascular system has been implicated in the pathogenesis of frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis and others neurodegenerative conditions such as HIV-induced neurocognitive disorder.

ALS patients also develop perfusion deficits in the fronto-parietal cortex.

The conventional model postulates that neurovascular coupling is mediated by vasodilator factors derived from neurons that directly relax the arterial smooth muscle cells. However, according to recent work, it seems that brain endothelial cells can also detect neuronal activity. Perhaps then the vasodilator signals first act on the brain endothelial cells before being relayed to the arterial smooth muscle cells.

Chow et al. explore this potential neurovascular coupling mediated by brain endothelial cells by adopting a very elegant approach. They focused on the somatosensory cortex of laboratory mice, where stimulation of the whiskers reliably triggers neural activity, dilated vessels and blood flow. They show that conventional detection of nitric oxide in smooth muscle cells is insufficient for complete neurovascular coupling.

Instead, the caveolae enriched with arteriolar cerebral endothelial cells are also necessary for efficient coupling. Using various cell-type specific mouse models and the overall knockout and overexpression gene, they confirm that the celloles in cerebral endothelial cells - not arterial smooth muscle cells - are necessary for neurovascular coupling.

These discoveries inspire fascinating questions to understand the biology of the cerebrovascular system in terms of health, aging and disease.

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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.