In Alzheimer’s disease, two brain pathological phenomena have already been well documented: the accumulation of beta-amyloid peptides and the modification of Tau, a protein, which is found as aggregates in neurons.© NIH/domaine public

Identifying genetic risk factors for Alzheimer’s disease is essential if we are to improve our understanding and treatment of it. Progress in human genome analysis along with genome-wide association studies[1] are now leading to major advances in the field. Researchers in Europe, the US and Australia have identified 75 regions of the genome that are associated with Alzheimer’s disease. Forty-two of these regions are novel, meaning that they have never before been implicated in the disease. The findings, published in Nature Genetics, bring new knowledge of the biological mechanisms at play and open up new avenues for treatment and diagnosis.

Alzheimer’s disease is the most common form of dementia, affecting around 1,200,000 people in France. This complex, multifactorial disease, which usually develops after the age of 65, has a strong genetic component. The majority of cases are thought to be caused by the interaction of different genetic predisposition factors with environmental factors.

Although our understanding of the disease continues to improve, there is no cure at this time. The medications available are mainly aimed at slowing cognitive decline and reducing certain behavioral disorders.

As part of an international collaboration, researchers from Inserm, Institut Pasteur de Lille, Lille University Hospital and Université de Lille conducted a genome-wide association study (GWAS) on the largest Alzheimer’s patient group set up until now[3], under the coordination of Inserm Research Director Jean-Charles Lambert.

Encouraged by advances in genome analysis, these studies consist of analyzing the entire genome of tens of thousands or hundreds of thousands of individuals, whether healthy or sick, with the aim of identifying genetic risk factors associated with specific aspects of the disease.

Using this method, the scientists were able to identify 75 regions (loci) of the genome associated with Alzheimer’s, 42 of which had never previously been implicated in the disease. “Following this major discovery, we characterized these regions in order to give them meaning in relation to our clinical and biological knowledge, and thereby gain a better understanding of the cellular mechanisms and pathological processes at play,” explains Lambert.

Highlighting pathological phenomena

In Alzheimer’s disease, two pathological brain phenomena are already well documented: namely, the accumulation of amyloid-beta peptides and the modification of the protein Tau, aggregates of which are found in the neurons.

Here, the scientists confirmed the importance of these pathological processes. Their analyses of the various genome regions confirm that some are implicated in amyloid peptide production and Tau protein function.

Furthermore, these analyses also reveal that a dysfunction of innate immunity and of the action of the microglia (immune cells present in the central nervous system that play a “trash collector” role by eliminating toxic substances) is at play in Alzheimer’s disease.

Finally, this study shows for the first time that the tumor necrosis factor alpha (TNF-alpha)-dependent signaling pathway is involved in disease[4].

These findings confirm and add to our knowledge of the pathological processes involved in the disease and open up new avenues for therapeutic research. For example, they confirm the utility of the following: the conduct of clinical trials of therapies targeting the amyloid precursor protein, the continuation of microglial cell research that was initiated a few years ago, and the targeting of the TNF-alpha signaling pathway.

Risk score

Based on their findings, the researchers also devised a genetic risk score in order to better evaluate which patients with cognitive impairment will, within three years of its clinical manifestation, go on to develop Alzheimer’s disease. “While this tool is not at all intended for use in clinical practice at present, it could be very useful when setting up therapeutic trials in order to categorize participants according to their risk and improve the evaluation of the medications being tested,” explains Lambert.

In order to validate and expand their findings, the team would now like to continue its research in an even broader group. Beyond this exhaustive characterization of the genetic factors of Alzheimer’s disease, the team is also developing numerous cellular and molecular biology approaches to determine their roles in its development.

Furthermore, with the genetic research having been conducted primarily on Caucasian populations, one of the considerations for the future will be to carry out the same type of studies in other groups in order to determine whether the risk factors are the same from one population to the next, which would reinforce their importance in the pathophysiological process.

[1] These studies consist of analyzing the entire genome of thousands or tens of thousands of people, whether healthy or sick, to identify genetic risk factors associated with specific aspects of the disease.

[2] All functional problems caused by a particular disease or condition.

[3] Here, the researchers were interested in the genetic data of 111,326 people who were diagnosed with Alzheimer’s disease or had close relatives with the condition, and 677,663 healthy “controls”. These data are derived from several large European cohorts grouped within the European Alzheimer & Dementia BioBank (EADB) consortium.

 [4] Tumor necrosis factor alpha is a cytokine: an immune system protein implicated in the inflammation cascade, particularly in tissue lesion mechanisms.

Salvador Dali liked to use short phases of sleep to stimulate his creativity. © Wiki Commons – Fair Use

What if a few minutes of sleep could trigger creativity? This is what suggests a study by researchers from Inserm and Sorbonne Université at the Brain Institute and the department of sleep medicine at Pitié-Salpêtrière Hospital AP-HP. Their findings have been published in Science Advances.

The inventor Thomas Edison is said to have taken short naps to spark his creativity. During them, he would hold a metal ball in each hand. Upon falling asleep, the balls would crash to the floor, waking him up just in time so that he could note his flashes of creativity. Other famous people also liked to use short phases of sleep to stimulate their creativity, such as Albert Einstein and Salvador Dali.

Inspired by this, the team of Inserm researcher Delphine Oudiette and her colleague Célia Lacaux at the Brain Institute and Pitié-Salpêtrière Hospital AP-HP wished to explore this very specific phase of sleep, to determine whether or not it affected creativity.

As part of their study, the team set the 103 participants math problems that could all be instantly solved using the same rule – of which the participants were unaware when starting the test. The subjects were allowed a first attempt at solving the problems. Those who had not found the hidden rule were invited to take a twenty minute nap inspired by Edison, holding an object in their right hand, before repeating the math tests.

“Spending at least 15 seconds in this very first phase of sleep after falling asleep tripled the chances of finding the hidden rule, due to the effect of the famous ‘Eureka!’ moment. ” An effect that disappeared if the subjects plunged into a deeper sleep,” explains Lacaux, first author of the study.

In parallel, the researchers revealed several key neurophysiological markers of this sleep phase that generates creativity.

During the onset of sleep, there is indeed a phase that is conducive to creativity. Activating it requires finding the right balance between falling asleep quickly and not falling asleep too deeply. These “creative naps” could be an easy and accessible way of stimulating our creativity in everyday life.

“The sleep onset phase has so far been relatively neglected by the cognitive neurosciences. This discovery opens up an extraordinary new avenue for future studies, particularly of the brain mechanisms of creativity. Sleep is also often seen as a loss of time and productivity. By showing that it is in fact essential to our creative performance, we hope to reiterate its importance to the general public. ” concludes Oudiette, Inserm researcher and last author of the study.

Astrocyte born during the infancy period (red) (7 to 20 days after birth) adhering to a GnRH neural cell body (green). The astrocytes’ processes are shown in white. © Vincent Prévot, Inserm.

Researchers from Inserm, Lille University Hospital and Université de Lille, at the Lille Neuroscience and Cognition laboratory, have discovered one of the mechanisms by which endocrine disruptors can alter reproductive function development from birth. At the neural level, they saw in animals how exposure to low doses of bisphenol A – a known endocrine disruptor – a few days after birth disrupts the integration of GnRH neurons within their neural circuit and alters their reproductive function regulation activity. The findings of this study have been published in Nature Neuroscience.

In mammals, reproduction is regulated by the GnRH neurons, a population of neurons that, during embryonic development, appears in the nose and then migrates to the hypothalamus in the brain. Being well established in the brain at birth, these neurons go on to control the various processes associated with reproductive function: puberty, acquisition of secondary sexual characteristics, and fertility in adulthood.

To perform their functions, the GnRH neurons must be surrounded by another type of neural cell: the astrocytes. The adhesion of the astrocytes to the GnRH neurons plays a decisive role in their integration within the neural network. The encounter between these two cell types takes place during the so-called “mini-puberty” period that begins one week after birth in mammals, when the GnRH neurons are first activated, and which is when the first sex hormone secretions occur.

“Failure of GnRH neurons to integrate during mini-puberty may lead to a predisposition to developing puberty and/or fertility disorders, and also potentially affect brain development, thereby leading to learning disorders or metabolic disorders, such as being overweight,” explains Vincent Prévot, Inserm Research Director and last author of the study.

But how does this encounter between GnRH neurons and astrocytes take place? According to the findings of this research, the astrocytes do not get there by chance but respond to molecular signals emitted by the GnRH neurons, which recruit them as soon as they appear in the hypothalamus.

Early bisphenol A exposure prevents communication between GnRH neurons and astrocytes

Going further, the researchers wanted to understand the importance of this meeting between astrocytes and GnRH neurons in the development of mammalian reproductive functions during the mini-puberty period. With recent studies having shown that the GnRH neural network is particularly sensitive to endocrine disruptors and that there is a link between the latter and puberty disorders, the researchers investigated the impact of exposure to one of these endocrine disruptors, bisphenol A, in rats.

“Despite its ban, bisphenol A continues to remain present in our environment due to the slow degradation of plastic waste, and also because people are still using food containers they had purchased before 2015. With the recycling of waste, bisphenol A from plastics produced before 2015 has also found itself in new products,” explains Prévot.

During the 10 days following their birth, the female rats received low-dose injections of bisphenol A. Using an astrocyte labelling technique, the researchers saw that, under the effect of bisphenol A, the astrocytes were unable to permanently adhere to the GnRH neurons. The absence of such a phenomenon

occurring between these nerve cells then led to delayed puberty and the absence of estrous cycles in the adult female rats (equivalent to the menstrual cycle in women), suggesting that reproductive functions are affected.

“Our findings suggest that early exposure to chemicals in contact with food, such as bisphenol A, can disrupt the onset of puberty and have a lasting impact on reproductive functions, by preventing GnRH neurons from building an appropriate and necessary environment in the hypothalamus for their role as fertility coordinator,” explains Ariane Sharif, lecturer at Université de Lille, who co-led the study.

Taking this research further, the scientists are now seeking to understand the exact mechanism by which bisphenol A prevents communication between GnRH neurons and astrocytes. One hypothesis is that bisphenol A acts directly on the astrocytes’ receptors, preventing them from adhering to the GnRH neurons. The research team is also interested in the action of bisphenol A on DNA and the traces it may leave.

Confocal microscopy image showing induced neurons (red with a yellow nucleus) expressing the NeuN neuronal marker (green) within an epileptic mouse hippocampus. © Extract from: Lentini et al., Cell Stem Cell, 2021.

Many central nervous system diseases are associated with the death of neurons without the brain being able to regenerate them. A phenomenon that is observed particularly in Parkinson’s disease, Alzheimer’s disease, following stroke, and in some forms of epilepsy. How can lost neurons be regenerated? This question has been tackled by a team of researchers from Inserm, CNRS and Université Claude Bernard Lyon 1 at the Stem Cell and Brain Research Institute, in collaboration with King’s College London. Using an animal model of epilepsy, the researchers have succeeded in transforming non-neuronal cells in the brain into new inhibitory neurons that reduce chronic epileptic activity by half. This research will in time make it possible to envisage a therapeutic application of this strategy. The findings of this study have been published in Cell Stem Cell.

Our brain generally lacks the regenerative capacity to replace lost or damaged neurons. The goal of regenerative medicine is to replace lost cells in order to correct the functional disorders associated with that loss. Direct cell reprogramming (as opposed to induced pluripotent stem cell reprogramming) has emerged as an innovative strategy that consists of “reprogramming” the identity of certain non-neuronal cells present within the affected brain to transform them into neurons. If this strategy is to be effective, many challenges need to be addressed. The new neurons must be integrated into the networks of surviving neurons and take over from those they replace in order to correct the pathological disorders.

This was the strategy explored in a new study published in the journal Cell Stem Cell. A team of researchers from Inserm, CNRS and Université de Lyon have succeeded in transforming glial cells of the brain into new neurons in a mouse model with mesial temporal lobe epilepsy, the most common form of drug-resistant epilepsy in humans.

Proliferation of glial cells: a cell source from which to generate neurons

In neuronal death, as observed in mesial temporal lobe epilepsy, the most common form of adult focal epilepsy, the glial cells present in the direct environment of the damaged neurons react by multiplying themselves, albeit without resolving the problem.

In the study, the researchers had the idea of taking advantage of this proliferation and using these extra glial cells. First, they had to identify genes making it possible to transform these glial cells into inhibitory neurons, whose loss plays a key role in the onset of seizures, in order to restore the balance of the neuronal activities that had been affected. The researchers therefore selected genes known for being involved in the genesis of these inhibitory neurons during development.

By forcing the expression of these genes, they were able to reprogram the identity of the glial cells to make them so-called “induced neurons” whose properties are comparable to those lost in the disease. Through stereotactic surgery[1], the genes were inserted directly into the brains of the mice at the sites of origin of the epilepsy using deactivated viral vectors that induce reprogramming of the glial cells. Within a few weeks, the vast majority of these gene-treated glial cells had transformed into new neurons.

Functional neurons integrated into the epileptic network

The results of the study show that the induced neurons adopt an identity of inhibitory neurons that present a set of molecular characteristics comparable to those of neurons having degenerated in epilepsy.

Using electrophysiological recordings, the scientists were able to confirm that they were indeed functional neurons, capable of inhibiting the neighboring neurons responsible for seizures, thereby reducing their activity. Then, by tracing connections between the neurons, they were able to determine that the induced neurons were fully integrated into the epileptic network but also more broadly in the brain.

Finally, thanks to electroencephalographic (EEG) recordings in the sites of origin of the seizures, the researchers were able to show, in the reprogrammed mice, that the seizures had reduced by half.

“These findings reveal the therapeutic potential of this cell reprogramming strategy in fighting a pathology such as mesial temporal lobe epilepsy. This represents a blessing in the specific case of this disease at a time when 30% of patients are refractory to pharmacological treatments,” explains Christophe Heinrich, the study’s designer.

Even if much remains to be done before this research can truly be applied to the treatment of patients, this study highlights the reprogramming of glial cells into neurons as a new strategy capable of modifying not just a disease such as epilepsy, but which also could be expanded to include other devastating brain diseases.

[1] Neurosurgery technique that uses a system of 3D coordinates in space for the precision-access of brain regions. 

In purple, the tanycytes that form the brain’s cellular gateway to the hormone leptin; in yellow, the appetite-inducing neurons and, in blue, the appetite-suppressing neurons. Leptin targets both neuron types, inhibiting the former and using its appetite-suppressant signal to activate the latter. © Vincent Prévot

Diabetes, a disease in which blood sugar levels remain too high for too long, can lead to health complications in the long term. Type 2 diabetes (T2D) accounts for 90% of cases. Patients are usually obese or overweight, with risk factors that include sedentary lifestyle and unbalanced diet. To increase their understanding of the disease, a team of researchers from Inserm, Université de Lille, and Lille University Hospital in the Lille Neuroscience and Cognition laboratory[1] has for several years studied the role of leptin, a hormone involved in appetite control that sends satiety signals to the brain. In a new study published in the journal Nature Metabolism, in addition to furthering scientific knowledge of the mechanism of satiety, the scientists developed a new mouse model of diabetes that will be useful for and relevant to future research in this area.

Leptin, the satiety or appetite-suppressant hormone, is secreted by the adipose tissue at levels proportional to the body’s fat reserves and regulates appetite by controlling the feeling of fullness.  It is transported to the brain by tanycytes – cells which it enters by attaching to the LepR receptors. Tanycytes are therefore leptin’s gateway to the brain, helping it to cross the blood-brain barrier and deliver satiety information to the neurons.

Previous research has revealed that such transport is impaired in subjects who are obese or overweight. This goes some way to explaining their dysfunctional appetite regulation given that it is more difficult for the information on satiety to reach the brain. In their new study, the researchers took a closer look at this transport mechanism, and more precisely the role played by the LepR receptors.

The key role of satiety hormone receptors in glucose management

In mouse models, the researchers removed the LepR receptor that is located on the surface of the tanycytes. After three months, the mice experienced a marked increase in their fat mass (which doubled over the period) as well as a loss of muscle mass (reduced by more than half). The total amount of weight gained was only fairly moderate. The scientists also regularly measured the animals’ blood sugar levels following the injection of glucose.

They found that in order to maintain blood sugar at normal levels (between 0.70 and 1.10 g/L), the mice secreted more insulin during the first four weeks of the experiment. Three months after removing the receptor, their ability to secrete insulin from the pancreas appeared to be exhausted.

Removing the LepR receptors and impairing leptin transport to the brain therefore led the mice to initially develop a pre-diabetic state. This occurs when the body releases more insulin than usual in order to control blood sugar. Then, in the longer term, the mice became unable to secrete insulin and as such unable to control their blood sugar levels. These data therefore suggest that impaired leptin transport to the brain via the LepR receptors plays a role in the development of type 2 diabetes.

In the last part of their research, the scientists reintroduced leptin to the brain and observed the immediate resumption of its pancreatic function-promoting action – particularly the ability of the pancreas to secrete insulin to regulate blood sugar. The mice quickly regained a healthy metabolism.

This study therefore elucidates the brain’s role in type 2 diabetes and also helps to further research into a disease that until then had not been considered to involve the central nervous system.

“We show that the brain’s perception of leptin is essential for the management of energy homeostasis[2] and blood sugar. We also show that blocking the transport of leptin to the brain impairs the functioning of the neurons that control pancreatic insulin secretion,” concludes Vincent Prévot, research director at Inserm and last author of the study.

The research team started by describing the mechanism by which leptin passes through the cell gate: tanycytes (Figure opposite: cells in yellow). These cells capture circulating leptin from the blood vessels which at that location have the particularity of letting it through (step 1). Whilst in the tanycyte, the leptin captured by LepR activates the EGF receptor (or EGFR) which itself activates an ERK signaling pathway (step 2), triggering its release into the cerebrospinal fluid (step 3). The leptin then activates the brain regions that convey its anorectic (appetite suppressant) action, as well as control of pancreatic function (step 4).

[1] This research was performed in collaboration with two laboratories at Institut Cochin and Université de Strasbourg as part of a project funded by the French National Research Agency (ANR) and two European laboratories, one at Lübeck University in Germany and the other at the University of Santiago de Compostela in Spain, within the framework of European Community funding. In addition, the Lille Neuroscience and Cognition laboratory is a member of LabEx EGID (European Genomic Institute for Diabetes) and DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).

[2] Stabilization, regulation in living organisms, of certain physiological characteristics (food intake, energy expenditure, etc.).

Primary culture of astrocytes © Inserm/Ruiz, Anne-Laure

Astrocytes are cells in the brain which have long been considered only as mere support cells for neurons. In recent years, the study of astrocytes has grown, gradually revealing their importance in brain function. Researchers from Inserm, CNRS and Collège de France at the Center for Interdisciplinary Research in Biology have now uncovered their crucial role in closing the period of brain plasticity that follows birth, finding them to be key to the development of sensory and cognitive faculties. Over the longer term, these findings will make it possible to envisage new strategies for reintroducing brain plasticity in adults, thereby promoting rehabilitation following brain lesions or neurodevelopmental disorders. This research has been published in Science.

Brain plasticity is a transient key period after birth in which the brain remodels the “wiring” of the neurons according to the external stimulations it receives (environment, interactions, etc.). The end – or “closure” – of this period marks the stabilization of the neural circuits, associated with efficient information processing and normal cognitive development. Plasticity is still possible in the future, although at a much lower level than at the beginning of life.

Problems occurring during the brain plasticity period could have major long-term consequences. For example, in the event of an eye condition preventing an individual from seeing correctly, such as strabismus (crossed eyes), the corresponding brain wiring will be permanently altered if it is not treated in time.

To remedy this, the researchers aim to remodel this wiring by identifying a therapy that would reintroduce brain plasticity, even once closure has occurred. To achieve this, they also seek to better characterize the biological mechanisms that underlie this closure.

Pioneering studies from the 1980s showed that transplanting immature astrocytes into the brains of adult animals reintroduced a period of major plasticity. The team of Inserm researcher and study coordinator Nathalie Rouach at the Center for Interdisciplinary Research in Biology (Inserm/CNRS/Collège de France)[1] took inspiration from this procedure to reveal the hitherto unknown cellular process responsible for the closure of plasticity.

Transplanting immature astrocytes to reintroduce brain plasticity

Through experiments on the mouse visual cortex, the researchers show that the presence of immature astrocytes is the key to brain plasticity. The astrocytes are then later involved in developing interneuron maturation[1] during the plasticity period, ultimately leading to its closure. This maturation process occurs via a novel mechanism involving the protein Connexin 30, of which the researchers found high levels in mature astrocytes during closure.

Could transplanting astrocytes into adult mice reintroduce brain plasticity?

To find out, the researchers cultured immature astrocytes from the visual cortex of young mice (1 to 3 days’ old). These immature astrocytes were transplanted into the primary visual cortex of adult mice, following which the activity of the visual cortex was evaluated after four days of monocular occlusion – a standard technique used to assess brain plasticity. They found that the mice transplanted with the immature astrocytes presented a high level of plasticity, unlike the control mice which did not receive the transplant.

 “This study is a reminder that in the neurosciences we must not only focus on neurons. The glial cells, of which the astrocytes are a subtype, regulate most of the brain’s functions. We realized that these cells have active roles. Glial cells are less fragile than neurons and so represent a more accessible means of acting on the brain, ” emphasizes Rouach.

[1]  The interneurons establish connections between an afferent neural network (which sends information to the central nervous system) and an efferent neural network (which sends this information to the organs responding to the stimulation)