Tanycytes (white) capture Tau protein (red) circulating in the cerebrospinal fluid and transport it along their extensions/arms, which pass through brain tissue and come into contact with blood vessels (green), into which they release this protein, which is involved in Alzheimer’s disease when it accumulates in the brain. © Vincent Prévot/Inserm

Patients with Alzheimer’s disease have common biological alterations, including abnormal accumulation of the Tau protein in the brain. The mechanisms behind this abnormality may be on the verge of being elucidated. In a new study, a research team from Inserm, the University of Lille, and Lille University Hospital has revealed for the first time the role of tanycytes in the equation. The dysfunction of these cells, already known to ensure certain exchanges between the blood system and the cerebrospinal fluid circulating inside the brain, could be responsible for the abnormal accumulation of Tau. After demonstrating the involvement of tanycytes in the transport of the Tau protein in animals and humans, the researchers discovered that the structure of tanycytes was degraded in the brains of patients who had died from the disease. These findings are published in the journal Cell Press Blue[1].

Alzheimer’s disease manifests itself through progressive memory impairment, executive function[2] decline, and impaired temporal and spatial orientation. It is caused by a slow and progressive degeneration of neurons in the hippocampus before spreading to the entire brain.

The diagnosis of Alzheimer’s disease can be based on measuring the presence of a protein in the cerebrospinal fluid (CSF), called Tau. In healthy individuals, the presence of Tau in the CSF is low: it is secreted by neurons and then eliminated in the blood. However, in people with the disease, the structure of Tau changes and it can no longer fulfill its normal role within neurons. It accumulates in a pathological form, disrupting brain function. This accumulation gradually leads to the degeneration and death of neurons, causing cognitive decline.

The mechanisms leading to the pathological accumulation of the Tau protein are not fully understood and are an active area of research.

For more than 20 years, Vincent Prévot, Inserm Research Director, and his team at the Lille Neuroscience & Cognition Research Center (Inserm/University of Lille/Lille University Hospital) have been studying the specific role of certain cells called tanycytes. These cells are known to facilitate essential exchanges between the brain and the rest of the body, particularly between the bloodstream and cerebrospinal fluid. For example, they detect and transport leptin (the satiety hormone) to the brain, and it is thanks to their function that the brain regulates appetite and energy balance.

In a new study, the team investigated for the first time the potential role of these cells in the pathological context of Alzheimer’s disease. They methodically followed several steps.

The researchers first validated that tanycytes were indeed involved in Tau transport. To do this, they injected the Tau protein into the cerebrospinal fluid and observed its path using fluorescence techniques. This initial experiment allowed them to visualize how Tau was captured in the cerebrospinal fluid by tanycytes and then transported along their extensions[3] to the blood capillaries.

From this observation, they hypothesized that tanycytes capture Tau and then release it and eliminate it into the bloodstream.

To test this second idea, the researchers studied the consequences of blocking tanycyte transport by genetically expressing botulinum toxin in the cells, which prevents them from functioning. The results showed a loss of Tau clearance from the CSF to the blood.

The researchers thus demonstrated for the first time in animals that tanycytes were the main route for clearing Tau proteins from the brain into the bloodstream.

At the same time, this time using mouse models with high levels of Tau in the CSF, they also showed that by blocking the activity of tanycytes, these mice developed the symptoms of dementia characteristic of Alzheimer’s disease, and more generally of tauopathy, a disease characterized by the accumulation of abnormal forms of the Tau protein [4], at an earlier stage.

To take their research further, the scientists studied the brains of people who had died with Alzheimer’s disease. These analyses confirmed the presence of Tau proteins in tanycytes, as had been shown in animals. They also noticed that the tanycytes were damaged: their extensions were fragmented, interrupting the communication pathway between the CSF and the blood. This alteration appears to be specific to Alzheimer’s disease—the researchers did not find it in the brains of patients with other types of dementia.

“Our results show for the first time the ability of tanycytes to transport Tau protein from the cerebrospinal fluid to the blood and the importance of these cells in the pathophysiology of Alzheimer’s disease. They suggest that the degradation of these cells contributes to Alzheimer’s disease,” explains Vincent Prévot.

“Tanycytes could therefore be considered a new therapeutic target. What if the good health of these cells could ultimately prevent the development of the disease?” concludes the researcher.

This work was conducted as part of a project funded by the European Community (ERC Synergy WATCH, No. 810331) and the Foundation for Medical Research (FRM, MND202310017920).

[1] Cell Press Blue is a new general science journal published by Cell Press.

[2] Mental abilities that enable you to plan a task, adapt your behavior, or cope with new situations.

[3] Tanycytes are cells that have long extensions, somewhat like “arms,” which extend from their cell bodies to reach the blood capillaries that establish communication between the hypothalamus and the anterior pituitary gland.

[4] Tauopathies include, among others, Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome…Les tauopathies comprennent, entre autres, la maladie d’Alzheimer, la paralysie supranucléaire progressive, le syndrome corticobasal…

© v2osk on Unsplash

Age-related macular degeneration (AMD) causes progressive vision loss in many elderly people, and no treatment is available for the so-called atrophic form of the disease. A neurostimulation system called Prima, including a subretinal implant, could change all that. The results of a clinical trial involving Inserm, Sorbonne University and CNRS – via the Institut de la vision -, the Hôpital Fondation Adolphe de Rothschild and the Hôpital national des 15-20 show that it partially restored sight in over 80% of participants with AMD, who recovered their ability to read letters, numbers and words. The results are published in the New England journal of medicine.

Age-related macular degeneration (AMD) is the world’s leading cause of blindness. It generally occurs after the age of 60. It is characterized by the destruction of the macula, the central part of the retina responsible for fine, detailed vision – the kind that enables us to read or recognize faces – while peripheral vision is preserved. There are two forms of AMD. Atrophic AMD is characterized by the progressive disappearance of the photoreceptor cells that capture light and transmit images to the brain, leading to the irreversible loss of central vision.

To date, there is no treatment for advanced atrophic AMD, but an international team involving the Institut de la vision (Inserm/CNRS/Sorbonne Université), the Fondation Adolphe de Rothschild, the Hôpital national des 15-20, Stanford University and Science Corporation, has developed a neurostimulation system designed to restore vision in these patients.

The device has already been tested in animals, and an initial clinical study at the Rothschild Foundation Hospital and 15-20, involving five patients, validated its suitability for human use. This time, the team has published efficacy and safety results for a larger number of patients at several European sites.

This new clinical study included 38 patients with atrophic AMD, recruited from 17 centers in five European countries, including several French sites. The average age of the patients was 78.9 years, with severely impaired vision. Their vision was assessed using standardized charts, i.e. the lines of letters found in any ophthalmologist’s office. To be included in the clinical trial, the result of this test had to be a logMAR score ≥ 1.2 for at least one of the two eyes, i.e. the virtual impossibility of reading the letters displayed.

Efficacy and safety

All participants received retinal implants, and their vision was assessed six and then twelve months after surgery. The primary efficacy endpoint set by the investigators was the proportion of participants with an improvement in visual acuity of 0.2 logMAR or more. A total of 32 people completed the study. Of these, 81% reached this threshold of improvement, reading at least 10 more letters in the vision chart after one year when wearing Prima than when wearing their natural vision, and with no change in peripheral vision. And 78% had a 0.3 logMAR improvement and read at least 15 more letters with the glasses. The maximum benefit was a gain of 1.18 logMAR; the patient was able to read 59 more letters. At one year, 84.4% of participants reported being able to read letters, numbers and words at home.

This trial was also designed to assess the adverse effects induced by this device and its implantation. A total of 26 serious events were observed in 19 participants, all of which had been anticipated in the risk analysis. Most were ocular hypertension, but there were also retinal detachments, holes in the macula and subretinal hemorrhages. The vast majority of cases occurred within the first two months, and 95% were rapidly resolved, either spontaneously or by medical intervention. Tolerance was considered good. Further follow-up is planned up to 36 months.

“The benefits far outweighed the adverse effects,” concludes José-Alain Sahel, senior author of this article and an international researcher affiliated with Inserm, the Institut de la vision (CNRS/Inserm/Sorbonne Université), the Hôpital Fondation Adolphe de Rothschild; the Hôpital national des 15-20; Sorbonne Université, Paris; and the University of Pittsburgh School of Medicine, Pittsburgh, USA. “Until now, other types of subretinal implants had been developed, with far less benefit. This is the first time that a system has enabled patients who have lost their central vision to read words and even sentences again, while preserving their peripheral vision”, he concludes.

Astrocytes are found throughout the brain. Each astrocyte is in contact with several neurons and more than 100’000 synapses. A new study shows that, at the microscopic level, dozens of synapses from distinct neural circuits gather around a single specialized astrocyte structure called a leaflet, which is capable of detecting and integrating the activities of multiple synapses. Right panel: 3D rendering of a real dataset by the 3D artist Rémi Greco.© Lucas Benoit/GIN

 A collaborative French-Swiss study reveals a previously unknown role for astrocytes in the brain’s information processing. Published in the journal Cell, the research shows that these glial cells are able to integrate signals from several neurons at once—a conceptual shift in our understanding of the brain.

The brain does not function via neurons alone. In fact, nearly half of the cells that make up the brain are glial cells, and among them, astrocytes occupy a special place. Their name comes from their star-shaped skeleton, but their external appearance is more reminiscent of certain nebular stars, with an irregular, filamentary contour that allows them to insert themselves into the smallest gaps between neurons, blood vessels, and other cells. They are thus in close contact with synapses, the communication hubs between neurons.

Since the 1990s, neuroscientists have therefore suspected that astrocytes actively participate in the transmission of information by using calcium as a messenger molecule. This small chemical component can trigger a cascade of reactions in the cell, including the release of molecular transmitters that can modulate synaptic activity. For these signals to occur, an internal structure called the endoplasmic reticulum (ER) is essential: it stores calcium and releases it under certain conditions. Despite numerous hypotheses, the exact roles of these calcium signals remained unclear, particularly in the minutest areas of astrocytes in direct contact with synapses, because they are particularly difficult to observe due to their tiny size. A research team bringing together universities of Lausanne (Unil) and Geneva (UNIGE), Inserm and Grenoble Alpes University (Grenoble Institute of Neuroscience, GIN), and the Wyss Center for Bio and Neuroengineering has just filled this gap.

Beyond the simple synapse

Until now, astrocytes were perceived as acting on the margins of neuronal synapses. The so-called “ tripartite synapse model ” attributed an auxiliary role to them: modulating activity between two neurons. But the current study reveals a much more central role: astrocytes do not simply interact with a single synapse – they simultaneously coordinate several synaptic inputs from different neurons achieving a new level of spatial and temporal integration of the information.

The study, published in Cell on September 24, reveals that specific extensions of the astrocyte membrane, dubbed leaflets, envelop the synapses, contain ERs, and are interconnected through tunnels called gap junctions to form a single functional domain. In each of these domains, a small amount of calcium is released each time a neighboring synapse is active. Thus, one single leaflet can integrate the signals from about then, or even more, different neurons. The domains then release larger amounts of calcium, mirroring the integration of the various neuronal signals received. This calcium in turn promotes the release of factors that can regulate communication between the synapses enclosed within the leaflet.

Far from being simple relays, the scientists thus consider astrocytes as active computational elements of the brain.

“We have demonstrated for the first time that astrocytes are not limited to responding to a single synapse, but can integrate signals from entire neural circuits. This opens the door to new cognitive functions carried out by these glial cells,” explains Andrea Volterra of Unil’s Department of Fundamental Neuroscience, honorary professor at the Faculty of Biology and Medicine and study co-director.

Exploring every corner of the brain

To observe these unprecedented interactions, the team combined two cutting-edge techniques: nanoscopic resolution volumetric electron microscopy  and an optical microscopy technique. “We developed it specifically for this study so that we could visualize calcium changes in very small volumes,” says Nicolas Liaudet, an engineer at UNIGE and co-author of the study. This approach made it possible to visualise the leaflets in their exact environment and to evaluate simultaneously their composition, connectivity, and dynamic role. “Our methodological synergy was key to achieve this new level of understanding,” indicates Karin Pernet-Gallay, Inserm research engineer, director of the Electron Microscopy Platform at the Grenoble Institute of Neurosciences and co-director of the study.

The leaflets, less than 250 nanometres in size, originate from the cell body of the astrocyte or from its main extensions, do not contain mitochondria, but possess fragments of the endoplasmic reticulum (ER) and the molecular machinery capable of generating calcium signals. They are close enough to synapses to respond to their signals and interconnected among each other to coordinate broader responses. By genetically removing part of the molecular machinery that enables calcium signalling in astrocytes, the researchers were able to demonstrate that tiny calcium signals originate in the leaflets themselves as a result of synaptic activity.

Andrea Volterra explains that the leaflets are, in a way, “biochemical control towers, independent from the rest of the astrocytes. They seem to be there to survey and coordinate the information travelling in each synaptic trajectory according to a higher-level plan.”

Cognitive and clinical functions to be explored

The study’s results show that astrocyte activity is correlated with neuronal signals in the synapses, but also that it is amplified when several neurons are active at the same time. This capacity for integration potentially makes astrocytes large-scale controllers of brain activity, rather than simple local regulators at the level of an individual synapse.

These discoveries offer new avenues for understanding higher brain functions such as memory, emotions, consciousness and decision making. They could also explain certain dysfunctions observed in brain pathologies.

“It is likely that astrocytes play a protective or aggravating role depending on the pathological context. We will now study their involvement in memory and neurocognitive degeneration such as Alzheimer’s disease,” concludes Andrea Volterra.

Motoneurones (stained by immunohistochemistry for ChAT) of the lumbar section of the spinal cord in ALS mouse models. Scale 100 mm © Simon J Guillot, Daniel Beckett ,Matei Bolborea

Amyotrophic Lateral Sclerosis (ALS), Charcot’s disease, or Lou Gehrig’s disease is a severe neurodegenerative disease that leads to progressive paralysis of muscles involved in voluntary movement. To date, no curative treatment exists. The disease is typically fatal within three to five years of onset. Researchers from Inserm and the University of Strasbourg, at the Center for Biomedical Research, have made progress in understanding the mechanisms underlying ALS. In a new study, they reveal that characteristic symptoms of the disease are preceded by sleep disturbances. Their findings suggest that sleep disorders appear before the onset of motor impairment and respiratory issues. The study highlights a previously unknown role of certain hypothalamic neurons in the emergence of these ALS-related sleep disturbances. Published in Science Translational Medicine, this research identifies new potential therapeutic targets in the brain and explores a novel class of molecules to counteract the effects of sleep deprivation.

ALS results from the progressive death of nerve cells known as motor neurons. This degeneration leads to rapid and progressive muscle atrophy, resulting in a loss of autonomy due to motor dysfunction and deficits. In most cases, respiratory muscle failure is the primary cause of death.

In recent years, research efforts have significantly advanced the understanding of the genetics and biology of ALS. However, pinpointing the precise mechanisms that initiate and sustain neuronal degeneration remains a challenge. Unraveling these mechanisms is a key research objective for the team led by Luc Dupuis and Matei Bolborea, both Inserm researchers at the Strasbourg Center for Biomedical Research (Inserm/University of Strasbourg).

As ALS progresses, it affects respiratory function, indirectly leading to sleep disturbances. However, it was unclear whether these disturbances could precede motor symptoms, as observed in several other neurodegenerative diseases like Parkinson’s and Alzheimer’s. When do these disturbances emerge? Are they a consequence of motor dysfunction? These questions were investigated by the team of Luc Dupuis and Matei Bolborea in close collaboration with the German Center for Neurodegenerative Diseases (DZNE) in Ulm.

In their latest research, the scientists collected and analyzed dozens of sleep recordings from individuals with ALS at different stages of the disease, comparing them to control groups.

One group consisted of ALS patients who had not yet developed respiratory symptoms. Another group included presymptomatic individuals carrying specific genetic mutations associated with the disease, meaning they were at increased risk of developing ALS.

The results indicated that both groups experienced similar sleep disturbances: increased wakefulness and a reduced amount of deep sleep compared to the control groups.

These findings suggest that sleep disturbances are present and observable long before the onset of motor symptoms—potentially several years in advance.

Restoring Sleep in ALS Patients

Following this discovery, researchers sought to determine the origin of these sleep disturbances in the brain. They focused on specific neurons in the hypothalamus known as orexin[1] neurons, which play a crucial role in wakefulness. Using ALS mouse models, the team observed the same types of sleep disturbances. They also discovered that neuronal circuits involving orexin neurons were disrupted due to the loss of supporting neurons as the disease progressed.

This led them to test an orexin-inhibiting compound found in an already approved sleep medication prescribed for insomnia[2]. Administering this drug to ALS-affected mice successfully restored sleep with a single oral dose. Furthermore, restoring the activity of neurons supporting orexin neurons led to motor neuron preservation after 15 days of treatment.

A clinical trial is currently underway to test this compound in ALS patients. The goal is to determine whether restoring sleep can influence the progression of the disease.

‘Our main objective was to unveil what happens in patients before they show any motor symptoms,’ explains Matei Bolborea, co-senior author of the study.‘ These discoveries about the timeline of symptoms allow us to reconsider the brain’s role—particularly the hypothalamus—in the onset of ALS and to explore new therapeutic targets.‘

Luc Dupuis, co-senior author of the study, adds: ‘Our team’s findings are significant on two levels. First, they shed light on a new timeline of ALS symptoms, prompting us to reevaluate the origins of the disease and the brain’s role in its development. Second, they offer a glimmer of hope for patients, as addressing the early manifestations of the disease might slow its otherwise extremely rapid progression.’

[1] Studies have shown, for example, that people with narcolepsy have fewer orexin neurons than others.

[2] Suvorexant® belongs to a class of drugs known as hypnotics, and is approved for sale in the USA.

Age-related macular degeneration (AMD) is the leading cause of visual disability in people over 50 years of age. © Adobe Stock

Age-related macular degeneration (AMD) is the leading cause of visual disability in people over 50 years of age. Improving the treatment offering for patients is a major challenge for research. In a new study, a team of researchers from Inserm, CNRS and Sorbonne Université at the Vision Institute[1] in Paris describes the efficacy of dopaminergic drugs in slowing the progression of one of the forms of the disease, namely the neovascular or ‘wet’ form which is characterised by the proliferation of dysfunctional blood vessels under the retina. These specific drugs are already used in the treatment of Parkinson’s disease. These findings have been published in The Journal of Clinical Investigation.

AMD  is a multifactorial disease of the retina that affects people over 50 years of age. It is when part of the retina – the macula – degenerates, with the potential loss of central vision. Although highly incapacitating, it never causes complete blindness since the peripheral part of the retina remains intact.

There are two forms of the disease whose prevalence is roughly equivalent: the neovascular form – known as the ‘exudative’ or ‘wet’ form and the atrophic – ‘advanced dry’ form (see box).

While there is currently no curative treatment for the dry form of the disease, the neovascular form can be slowed down by regular injections administered directly into the eye (intravitreal injections). Although necessary, these injections can represent a major therapeutic burden due to their frequency, which is monthly or bimonthly depending on the course of the disease. It is therefore useful to continue to identify new alternatives for patients.

Medicines for Parkinson’s

Previous epidemiological studies have already shown a possible association between Parkinson’s disease and a reduced risk of neovascular AMD[2]. In this new study, researchers from Inserm, CNRS and Sorbonne Université at the Vision Institute explored the underlying mechanisms that would explain this potential protection.

In cell and animal models, the scientists have shown that L-Dopa, a drug in the dopaminergic family[3] used to treat Parkinson’s disease, activates a specific receptor in the brain known as DRD2. This activation blocks the formation of new blood vessels in the eye, which is a key process in the development of neovascular AMD.

To go further, the team then analysed the health data of over 200 000 patients with neovascular AMD in France[4]. They showed that those patients who took L-Dopa or other drugs that inhibit the DRD2 receptor (DRD2 agonists) to treat their Parkinson’s disease developed neovascular AMD later in life and required fewer intravitreal injections. Indeed, such patients developed the disease at 83 years of age instead of 79 years of age for the other patients.

‘These findings open up new perspectives for patients with wet AMD. We now have a serious avenue for delaying the progression of this disease and reducing the burden of current treatments’, explains Florian Sennlaub, Inserm Research Director at the Vision Institute (CNRS/Sorbonne Université/Inserm).

Thibaud Mathis, university professor and hospital practitioner in the ophthalmology department of Croix-Rousse Hospital-Hospices civils de Lyon, and researcher at Université Lyon 1, as well as at the Vision Institute, agrees: ‘These findings suggest that dopaminergic drugs, beyond their role in Parkinson’s disease, could have a beneficial effect in the prevention and treatment of neovascular AMD.’

While more in-depth clinical studies will be needed to confirm these findings and evaluate the efficacy and safety of these drugs in the treatment of AMD, this discovery opens up encouraging new perspectives for the fight against the neovascular form, offering hope of a more effective and less burdensome treatment for patients.

[1]This research is the result of collaboration with teams from Université de Lyon, Lyon University Hospital, Université de Bourgogne and the Brain Institute in Paris.

[2]Levodopa Is Associated with Reduced Development of Neovascular Age-Related Macular Degeneration, Max J Hyman et al. Ophthalmology retina 2023

[3]Dopaminergic drugs provide the dopamine needed for the brain to function. In Parkinson’s disease, dopamine reduces the intensity of tremor, rigidity and akinesia.

[4] Data from the French national health information database (Système National des Données de Santé [SNDS]).

In red, the increased A2A receptors in the neurons of a mouse hippocampus. In blue, the cell nuclei (DAPI staining). © Émilie Faivre

In France, 900 000 people have Alzheimer’s disease or a related condition. The risk of developing Alzheimer’s depends on genetic and environmental factors. Among these factors, various epidemiological studies suggest that the regular consumption of moderate amounts of caffeine slows age-related cognitive decline and the risk of developing the disease. In a new study[1], researchers from Inserm, Lille University Hospital and Université de Lille at the Lille Neuroscience and Cognition research centre have taken a step further in understanding the mechanisms underlying its development. They have shown that the pathological increase in certain receptors in the neurons at the time of disease onset promotes a loss of synapses, and as such the early onset of memory impairments in an animal model of the disease. Their findings also confirm the utility of conducting clinical trials to measure the effects of caffeine on the brains of patients at an early stage of the disease. These findings have been published in Brain.

Alzheimer’s disease is characterised by disorders of memory, executive function and orientation in space and time. It results from the slow degeneration of the neurons, which begins in the hippocampus (essential for memory) and then spreads to the rest of the brain. Sufferers present two types of microscopic brain lesions: senile plaques (or amyloid plaques) and neurofibrillary degeneration (or tau pathology), which contribute to neuron dysfunction and disappearance^[2].

Studies had already shown that the expression of certain receptors, known as A2A receptors, was found to be increased in the brains of patients affected by Alzheimer’s disease in the hippocampus. However, the impact of such dysregulation on the development of the disease and associated cognitive disorders had remained unknown until now. In a new study, a team led by Inserm researcher David Blum took a closer look at this question.

The scientists were able to reproduce an early increase[3] in the expression of the adenosine A2A receptors, as observed in the brains of patients, in a mouse model of Alzheimer’s disease that develops amyloid plaques. The objective was to assess the consequences of this increase on the disease and to describe the mechanisms involved.

The results of their research show that the increase in A2A receptors promotes the loss of synapses[4] in the hippocampus of ‘Alzheimer’s mice’. This causes the early onset of memory impairments in the animals. The scientists then showed that a dysfunction of certain brain cells – the microglial cells, partly responsible for the brain inflammation seen in the disease – could be involved in the loss of synapses, in response to an increase in the A2A receptors.

Similar mechanisms had already previously been described by the team, this time in another model of the disease developing tau lesions[5].

‘These findings suggest that the increased expression of the A2A receptors alters the relationship between neurons and microglial cells. This alteration could be the cause of an escalation of effects leading to the development of the memory impairments observed,’ explains Émilie Faivre, co-last author of the study and researcher at the Lille Neuroscience and Cognition centre (Inserm/Université de Lille/Lille University Hospital).

Caffeine: An interesting treatment avenue for the early prevention of cognitive decline?

Several studies had already suggested that regular and moderate caffeine consumption (equivalent to 2 to 4 cups of coffee per day) could slow the cognitive decline associated with ageing and the risk of developing Alzheimer’s disease.

In 2016, the same research team had described one of the mechanisms by which caffeine could have this beneficial effect in animals, reducing the cognitive disorders associated with Alzheimer’s disease. The scientists then showed that the effects of caffeine were linked to its ability to block the activity of the adenosine A2A receptors – the same receptors whose expression is abnormally increased in the brains of people with Alzheimer’s[6].

‘By describing in our new study the mechanism by which the pathological increase in A2A receptor expression causes a cascade of effects leading to a worsening of memory impairment, we confirm the relevance of therapeutic avenues that could act on this target. We therefore once again emphasise the utility of testing caffeine in a clinical trial on patients with early forms of the disease. Indeed, we can imagine that by blocking these A2A receptors, whose activity is increased in patients, this molecule could prevent the development of memory impairment or even other cognitive and behavioural symptoms,’ continues Blum, Inserm Research Director and co-last author of the study.

A phase 3 clinical trial[7], run by Lille University Hospital, is ongoing. Its objective is to evaluate the effect of caffeine on the cognitive functions of patients with early to moderate forms of Alzheimer’s disease.

[1]This research was supported by Fondation Alzheimer, FRM, ANR, CoEN (LICEND), Inserm, Université de Lille, Lille University Hospital and labEx Distalz (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer’s Disease) as part of France’s Investments for the Future programme. 

[2] Read the Inserm Report on Alzheimer’s disease and consult its Graphic novel which explains the cellular and molecular mechanisms involved in its development. 

^[3] At a stage during which the animals are not yet usually suffering from memory impairments.

[4] Zones that enable the transmission of information between neurons.

[5] Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor, Brain, Volume 142, Issue 11, November 2019, Pages 3636–3654, https://doi.org/10.1093/brain/awz288

[6] Read the press release

[7] The CAFCA phase 3 clinical trial is being conducted by neurologist Thibaud Lebouvier, in conjunction with the LilNCog laboratory and the Lille University Hospital Memory Centre. https://www.cafca-alzheimer.fr/

Visualisation, au sein de la barrière hémato-encéphalique, des macrophages associés au système nerveux central (CAM, en jaune), à l’interface entre un vaisseau sanguin (magenta) et des astrocytes (cyan), cellules de soutien des neurones en forme d’étoile. © Dr Damien Levard

Ageing greatly increases the risk of ischaemic stroke. A team of researchers from Inserm, Caen-Normandy University Hospital and Université de Caen Normandie have looked at the role that immune cells known as central nervous system-associated macrophages (CAMs) could play in the neurological damage that occurs following a stroke. Their research shows that during the course of ageing these cells acquire a key role in regulating the immune response triggered in the wake of a stroke.  This research, to be published in Nature Neuroscience, highlights the importance of the presence of these cells at the interface between the blood and the brain in maintaining brain integrity.

The most common type of stroke is ischaemic stroke, which is caused by a blood clot obstructing an artery in the brain. Age is a major risk factor, with the risk of ischaemic stroke doubling every 10 years from the age of 55.

Ischaemic stroke is followed by inflammatory processes in the brain that may aggravate neurological lesions. Central nervous system-associated macrophages (CAMs) are immune cells located within the blood-brain barrier[1], at the interface between the blood circulation and the brain parenchyma[2]. Normally, the role of the CAMs is to monitor their environment, clean it of debris and other molecules from the brain parenchyma, as well as molecules from the blood that cross the blood-brain barrier, and alert other immune cells to the presence of pathogens. Little studied so far, they are nevertheless in an ideal anatomical situation to detect and react to external inflammatory signals and protect the brain parenchyma.

A research team from the Physiopathology and Imaging of Neurological Disorders unit (Inserm/Université de Caen Normandie) led by Marina Rubio, Inserm researcher, and Denis Vivien, professor and hospital practitioner at Université de Caen and Caen-Normandy University Hospital and head of the unit, has studied in mice and in human brain tissues how the role of CAMs evolves during ageing and their potential involvement in regulating the inflammatory response occurring in the brain after an ischaemic stroke.

First, the scientists sought to characterise how the role of CAMs and their biological environment change during the course of ageing. They observed that while the number of CAMs did not change with age, their functions did, with the appearance on their surface of the MHC II receptor – a specific molecule that plays a major role in the communication between immune cells (e.g. to coordinate the immune response to a pathogen). At the same time, the blood-brain barrier, which is intact in young brains, becomes more porous, allowing certain immune cells to pass from the blood to the parenchyma.

‘These observations suggest that the CAMs are capable of adapting their activity to the individual’s stage of life, state of health and the brain region in which they are located,’ specifies Rubio. Thus, in order to compensate for the age-related increase in blood-brain barrier porosity, they would strengthen their ability to communicate with other immune cells through further expression of the MHC II receptor. ‘Following an ischaemic stroke, this could help prevent an excessive immune response that would have more serious neurological consequences,’ adds the researcher.

The team then looked at the impact of these functional changes on the immune response in the brain parenchyma following an ischaemic stroke. To do this, it compared what happened after a stroke in a normal elderly mouse brain with what happened in the absence of CAMs or when their MHC II receptor was inhibited.

In these last two models, the researchers observed that during the acute phase of the ischaemic stroke and also in the days that followed, more immune cells from the blood crossed the blood-brain barrier, indicating its increased permeability coupled with an exacerbated immune response. This phenomenon was accompanied by a worsening of the neurological damage caused by the stroke.

‘These findings suggest that the CAMs acquire, during the course of ageing, a central role in orchestrating immune cell traffic after an ischaemic stroke, explains Vivien. And that, thanks to their capacity for adaptation, they ensure the ongoing close monitoring of the integrity of the blood-brain barrier and the intensity of the inflammatory response.’

The MHC II receptor located on the CAMs appears to be involved in this modulation as well as in the limitation of stroke-related neurological damage.

Further research for this team will aim to better understand the molecular mechanisms involved in the dialogue between the CAMs and the cells lining the internal wall of the brain’s blood vessels.

‘The objective will ultimately be to identify and develop new therapeutic targets that could enable the brain’s immune response to be modulated in a manner appropriate to each patient after a stroke,’ concludes Rubio.

[1]The blood-brain barrier separates the brain’s blood vessels from the brain parenchyma. It acts as a highly selective filter capable of allowing the passage of nutrients essential for the brain while protecting the parenchyma from pathogens, toxins and hormones circulating in the blood and which are likely to succeed in exiting the blood vessels. 

[2]The parenchyma is the functional tissue of the brain directly involved in neural activities and the transmission of nerve impulses. It is surrounded by the perivascular spaces and the meninges where the CAMs reside.

© AdobeStock

Because of their cyclical rhythm and similar durations, the menstrual and lunar cycles have often been assumed to be linked, despite no solid evidence so far to support this. To gain a better understanding of the origin of the rhythmic regularity of the menstrual cycle, an international research team involving Inserm, CNRS and Université Claude Bernard Lyon 1 compared a large amount of data on cycles collected from studies conducted in Europe and North America. Its findings show that the menstrual cycle is finely regulated by an internal clock, which in turn is occasionally influenced by the lunar cycle. This research, to be published in Science Advances, argues in favour of further study of this potential link, to identify the potential relevance of chronobiology in the treatment of fertility disorders.

The average length of a typical human ovarian cycle, or menstrual cycle, is 29.3 days, varying from one person to another and from one cycle to another within the same person. It begins on the first day of menstruation and consists of three phases, each dedicated to the realization of a specific process linked to ovulation, which occurs around Day 14 of the cycle.

Some studies have suggested that each phase may be influenced by an internal clock, the disruption of whose rhythm is associated with irregularities in the menstrual cycle.

In humans, the most well-known internal clock is the circadian clock, which is very close to 24 hours and maintains the sleep-wake cycle and the various physiological rhythms. It is synchronised with the day-night cycle under the influence of light. When the circadian clock is disrupted – such as with jet-lag – it takes a few days to return to its normal rhythm, resynchronising with the new day-night cycle.

In the case of menstrual cycles, the involvement of an internal clock could manifest in a similar way: the cycle length should be highly stable within individuals and, if disrupted, its optimal rhythm should be restored by mechanisms of adaptation through synchronisation with external conditions.

So what could this ‘external synchroniser’ be? One recurring theory suggests that the lunar cycle could play this role, but scientific evidence is lacking to date.

An international research team led by Claude Gronfier, Inserm researcher at the Lyon Neuroscience Research Centre (Inserm/CNRS/Université Claude Bernard Lyon 1), has investigated the potential existence of an internal biological clock that would regulate the menstrual cycle and which may be synchronised with the lunar cycle. Using a large database of menstrual cycles collected in European and North American studies, the team was able to compare a total of approximately 27,000 menstrual cycles in 2,303 European women and approximately 4,800 cycles in 721 North American women.

The researchers began by examining the stability from one menstrual cycle to another at an individual level, by comparing the lengths of successive cycles. They observed that the average length of each participant’s cycle was stable overall, even though out of a series of successive cycles some were longer or shorter than that person’s ‘standard’ cycle.

‘These observations suggest the existence of a mechanism that corrects the difference between the length of the current cycle and that of a typical menstrual cycle in the person concerned, explains René Écochard, first author of the study, a doctor at the Hospices Civils de Lyon and professor at Université Claude Bernard Lyon 1. A few shorter cycles could therefore compensate for a series of a few longer cycles so that the total length of the cycle is around the usual length of the menstrual cycle. The length of a cycle could therefore depend on the length of previous cycles.’

‘The observation of this phenomenon argues in favour of the existence of an internal clock that finely regulates menstrual cycles, itself synchronised by a cyclical environmental event,’ adds Gronfier.

Secondly, the research team looked at the potential relationships between the onset of menstruation in the cycles studied and the phases of the moon at the time the data was collected.

It was able to observe an occasional but significant association between the menstrual cycle and the lunar cycle with, however – and without this research being able to explain its cause – a major difference between the European cohorts and the North American cohort: in the European cohorts, the cycle began more often during the waxing phase of the moon, whereas in the North American cohort it began more often at full moon.

‘Despite this astonishing difference, which we are unable to explain at present, the links identified in this research between the lunar and menstrual cycles, through their proximity to certain phenomena that we observe in chronobiology, suggest that the periodicity of menstruation and ovulation could be influenced, in a modest but significant way, by the lunar cycle,’ adds Gronfier.

These findings therefore argue in favour of an internal clock system with a near-monthly rhythm, synchronised to a small extent by the lunar cycle. However, they need to be studied in more depth and confirmed by laboratory studies and larger epidemiological studies.

‘Thanks to smartphone apps for recording cycles, the emergence of large databases containing information on the cycles of several hundreds of thousands of women could provide new opportunities for studies,’ says Écochard.

‘Confirming the existence of an internal clock coordinating the menstrual cycle, as well as the mechanisms involved in its synchronisation, could make it possible to apply personalised “circadian” medicine approaches – which are already used in oncology and for the treatment of sleep disorders or depression, for example – to problems such as ovulation and fertility disorders,’ concludes Gronfier.

Noradrenergic neurons in the mouse locus coeruleus whose dysfunction contributes to cortical hyperexcitability in ALS. © Caroline Rouaux

Amyotrophic lateral sclerosis or Charcot’s disease is a neurodegenerative disease that results in progressive paralysis and subsequent death. Diagnosing it is difficult and no curative treatment exists to date, making these challenges for research. In a new study, Inserm researcher Caroline Rouaux and her team at the Strasbourg Biomedical Research Centre (Inserm-Université de Strasbourg), in collaboration with researchers from Ludwig Maximilian University in Munich, CNRS and Sorbonne Université, show that electroencephalography could become a diagnostic and prognostic tool for the disease. Thanks to this type of examination, the scientists were able to reveal an atypical brain wave profile that could prove to be specific to the disease. Through this research, published in Science Translational Medicine, a potential therapeutic target has also been discovered. Fundamental advances that could ultimately benefit patients.

Amyotrophic lateral sclerosis (ALS), otherwise known as Charcot’s disease, remains a veritable challenge for clinicians. This neurodegenerative disease, which most often develops between the ages of 50 and 70, leads to progressive paralysis and death within just two to five years. It is caused by the death of the motor neurons – the nerve cells that control the muscles, both in the brain (central motor neurons) and in the spinal cord (peripheral motor neurons).

Diagnosing ALS is difficult because its initial signs vary from person to person: weakness or cramps in an arm or leg, trouble swallowing or slurred speech, etc. In addition, there is no biomarker specific to the disease. Therefore it is diagnosed by ruling out other conditions that can lead to motor disorders, which usually takes one to two years after the onset of symptoms, delaying the deployment of therapeutic measures and reducing the chances of inclusion in clinical trials at an early stage.

It was with the aim of shortening this time frame that Caroline Rouaux’s team at the Strasbourg Biomedical Research Centre, in collaboration with the teams of Sabine Liebscher in Munich and Véronique Marchand-Pauvert, Inserm researcher in Paris, tested the use of electroencephalography¹. This inexpensive and easy-to-use technique involves placing electrodes on the surface of the skull to record brain activity in the form of waves.

The examination performed in subjects with ALS and in corresponding animal models revealed an imbalance between two types of waves associated with excitatory and inhibitory neuron activity, respectively. This imbalance, in favour of greater excitatory neuron activity to the detriment of inhibitory neurons, reflects cortical hyperexcitability.

‘This phenomenon is no surprise and had already been described with other investigation methods, but these are rarely used due to being difficult to implement and only work at the very beginning of the disease. Electroencephalography, however, is minimally invasive, very inexpensive, and can be used at different times during the disease. In addition, the atypical brain wave profile revealed by electroencephalography could prove to be specific to the disease,’ explains Rouaux, Inserm researcher and last author of the study.

Indeed, analysis of the electroencephalographic recording of the brain’s electrical activity reveals various types of brain waves of differing amplitudes and frequencies. One of these, called the theta wave, reflects the activity of the excitatory neurons that transmit messages stimulating neurons, while another wave, gamma, reflects that of the inhibitory neurons that block the transmission of nerve messages.

The study reveals that in humans and animals with ALS, the interaction between these two wave types is atypical, revealing an imbalance between the excitatory and inhibitory activities. Not only was this imbalance found in all the subjects tested, but the scientists also showed that the more the symptoms of the disease progress, the greater the imbalance. In addition, this atypical wave pattern was detected in animals even before the onset of the first motor symptoms.

If these initial findings are confirmed, electroencephalography could in the future serve as a prognostic tool for already-diagnosed patients in order to evaluate, for example, the response to a medication, or even as a diagnostic tool in the event of symptoms suggestive of the disease.

In the second part of this research, the scientists were able to study, in patients and mice, the mechanisms behind the hyperexcitability observed. First, they measured the levels of the different neuromodulators produced by the neurons to communicate with each other, and found a deficiency in one of them: noradrenaline was present in smaller amounts in the brains of the patients and mice with ALS compared to healthy brains.

To verify the role of noradrenaline, they blocked the production of this neuromodulator in healthy animals, and showed that doing so causes cortical hyperexcitability, such as that observed in the disease. And conversely, by administering molecules that stimulate the action of noradrenaline in a mouse model of ALS, the scientists reduced the hyperexcitability and restored brain activity equivalent to that of healthy mice.

‘This discovery could mark the opening of a new therapeutic avenue in ALS provided that cortical hyperexcitability is indeed associated with disease progression. Indeed, while we have seen an association between the two in our study, no causal link has been established for the moment. This is what we will be checking in the coming months.’ concludes Rouaux.

 

¹ Electroencephalography is commonly used for research purposes in neurology but also in clinical practice. The examination provides information on brain activity in the event of sleep disorders, after a stroke, or even in the case of coma. It can also be used to diagnose encephalitis, epilepsy or confirm brain death.

Learning mindfulness meditation improves self-compassion, while health education promotes an increase in physical activity. © AdobeStock

A team from Inserm and Université de Caen Normandie, in collaboration with researchers from the University of Jena (Germany) and University College London (UK), has studied the potential benefits of meditation and health education interventions in people who feel that their memory is in decline. This research was performed as part of the European H2020 Silver Santé Study programme coordinated by Inserm[1]. It shows that learning mindfulness meditation improves self-compassion, while health education promotes an increase in physical activity. These findings, published in Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, propose new avenues to support healthier ageing.

‘Subjective cognitive decline’ is when people feel that their cognitive faculties have deteriorated without this being apparent in standard cognitive tests. Studies have shown that such people have a higher risk of developing actual cognitive decline.

Previous studies had concluded that mindfulness meditation and health education (a practice in which people implement preventive measures and actions that are beneficial for their health) had a positive impact, which was still present six months later, on anxiety in people reporting subjective cognitive decline.

More generally, self-compassion (feeling of kindness toward oneself, having a sense of common humanity, and having an awareness of negative thoughts and feelings without over-identification) and exercise have previously been associated with better mental health, itself associated with improved general health, well-being, and quality of life.

A European research group coordinated by Julie Gonneaud, Inserm researcher at the Physiopathology and Imaging of Neurological Disorders laboratory (Inserm/Université de Caen Normandie), Olga Klimecki, researcher at the University of Jena (Germany), and Nathalie Marchant, researcher at University College London (UK), studied the impact of eight weeks of mindfulness meditation and health education courses on self-compassion and physical activity in people reporting subjective cognitive decline.

The trial included 147 patients from memory clinics in France, Spain, Germany and the UK. One group took meditation classes for eight weeks, while the other took health education classes. The impact of the interventions was evaluated using blood tests, cognitive assessments and questionnaires.

The researchers observed that the participants who did the mindfulness meditation training showed an improvement in their self-compassion. The participants who did the health education training showed an increase in their physical activity. These changes were still present six months later.

These findings support complementary effects of mindfulness meditation and participation in health education programmes on certain factors contributing to improved mental well-being and lifestyle in older adults reporting subjective cognitive decline.

The fact that these improvements appear to be sustained after six months of follow-up suggests that these new skills and habits have been incorporated into the participants’ lives.

According to Marchant, who led the trial, ‘more and more people are living to an advanced age, and it is crucial that we find ways to support the mental and physical health of older adults.’

‘Self-compassion can be of great importance to the elderly. It could improve psychological well-being in order to promote healthy ageing,’ adds Klimecki. ‘Our findings are an encouraging first step towards a mindfulness-based intervention that could be used to strengthen self-compassion in older adults. ‘

Gonneaud adds: ‘Although physical activity has been scientifically associated with better physical, cognitive and mental health, how to promote it in everyday life remains a challenge. Given the particularly harmful effect of a sedentary lifestyle on the health of ageing populations, showing that health education intervention programmes can strengthen commitment to physical activity among the elderly is particularly promising for promoting healthy ageing,‘ she concludes.

[1] This research is funded by the European Union and forms part of the SCD-Well study of the H2020 Silver Santé programme (www.silversantestudy.eu), which has received 7 million euros in funding and is coordinated by Inserm. The Silver Santé study, funded for a five-year period, examines whether mental training techniques, such as mindfulness meditation, health education, or language learning, can help improve the mental health and the well-being of the ageing population.