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The theory of infectious origin of the Alzheimer's disease

The hypothesis that Alzheimer's disease has an infectious origin, has a long and controversial history. The data at the origin of this hypothesis are contradictory and mainly associative in nature, without it being possible to demonstrate a causal link. Interest in this theory has been renewed, however, by several recently published observations. In the section Viewpoint de la revue Nature Reviews Neurology, Ben Readhead, a researcher at the Biodesign Institute's ASU-Banner Center for Research on Neurodegenerative Diseases, joined several distinguished colleagues to discuss the idea that bacteria, viruses or other infectious pathogens can play a role in Alzheimer's disease.

A hypothesis that has never been favored by researchers

This hypothesis may have been rejected too quickly. For example, microorganisms do not only cause acute illnesses, in fact certain microorganisms can hide in the body for decades in latent form, causing damage intermittently or after long periods of silence.

In addition, being infected does not necessarily mean being symptomatic. For example, out of the millions of people infected with Mycobacterium tuberculosis, only about a tenth of them will develop tuberculosis. Likewise, most people infected with HSV1 do not develop cold sores so it is possible that asymptomatic carriers of this virus were often mistakenly included in the control groups. It should also be noted that many viruses of the Herpes family (HSV1, HSV2, VZV) live preferentially in neurons.

A role for an infectious agent - in particular the herpes simplex 1 virus (HSV1) - in Alzheimer's disease (Alzheimer's disease) was proposed about 30 years ago based discovery of HSV1 DNA in the brain tissue of a large proportion of the elderly, followed by evidence that e the virus confers a high risk of disease to carriers of the ε4 allele of the gene apolipoprotein E (APOE * ε4).

Shortly after the detection of HSV1 DNA, two different species of bacteria, Borrelia burgdorferi and Chlamydia pneumoniae, were implicated in Alzheimer's disease, and a third species, Porphyromonas gingivalis, was recently added to the list.

Doubts remain, however

Nevertheless, it is known that an acute end-of-life infection, such as pneumonia, can cause a dramatic increase in the amount of microorganisms in the brain. They will then be detected post-mortem but that does not mean that these microorganisms are at the origin of the Alzheimer's disease. In addition, the issue of reverse causation is never really addressed: For example, clinical Alzheimer's disease can lead to poor dental hygiene and, therefore, damage to the oral microbiome.

Indeed, there are many challenges to prove the theory of microbial origin of Alzheimer's disease. A potential challenge is that each drug has a relatively narrow spectrum of antimicrobial activity. However, since a large number of microorganisms have been associated with Alzheimer's disease by a range of researchers, it would be difficult to interpret what a negative result in a clinical trial would mean, which would necessarily use a specific antimicrobial.

Another problem is the duration of the disease. We know that the underlying pathology of Alzheimer's disease begins 20 years or more before the onset of symptoms. So, how to prove that an infectious process that occurred decades before the onset of symptoms, really contributed to the disease process?

One may also wonder why bacteria or viruses would escape the innate innate immune defense mechanisms, which are responsible for protecting the brain against such an invasion.

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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.

Technologies to study neural activity

Recording the activity of a sufficient number of neurons at significant time scales and spatial distributions is one of the main challenges for a better understanding of how neural ensembles work.

Optical methods are increasingly used because they allow activity over a large area to be monitored from the same layer of brain tissue. In addition, they are inherently limited to recording from superficial structures of the brain or require the use of probes or surgery to provide access to deep brain regions.

A number of innovations have been made in electrical recording using flexible materials on the surface of the brain, and microelectrodes have long been the norm, but their number of channels is limited due to connection, volumetric displacement and tissue damage.

At the same time, electronics continue to evolve at a rapid pace, but few of these technological improvements make their way to neuroscience in vivo.

A new strategy for interfacing chips with three-dimensional micro-wire arrays

In this article, the authors report a new strategy to take advantage of the scalability and power of electronic components combined with a 3D neural interface.

This neural interface consists of a bundle of isolated micro-wires coupled perpendicularly to imaging networks such as those found in camera chips. enter image description here

By organizing them into bundles, the authors control the three-dimensional structure of the distal end, with a robust parallel contact plane on the proximal side which is coupled to an array of pixels.

The density of the microwires for the proximal end and the distal end can be independently adjusted, allowing wire-to-wire spacing to be customized as required.

Design and Manufacturing

enter image description here

  • (A) Procedure for manufacturing bundles of micro-wires.
    • (i) The individual micro-wires are electrically insulated with a robust ceramic or polymer coating.
    • (ii) A sacrificial layer is applied to the wires to ensure spacing.
    • (iii) The tips of the micro-wires can be shaped with an angular tip..
    • (iv) The wires are then grouped together by winding the wire or by mechanical aggregation. The threads pile up naturally in a honeycomb network.
    • (v) The bundle is infiltrated with biomedical epoxy to hold the wires together, then the upper (proximal) end is polished to mate with the CMOS chip.
    • (vi) The proximal end is etched from 10 to 20 μm to mate with the CMOS chip and the distal end of the wires is released by etching.
    • (B) An electron microscope backscatter view of an individual microwire.
    • (C) The wires are grouped in a structure in honeycomb and epoxy is infiltrated in between to fill in the gaps.
    • (D) Proximal end of a 177 bundle wires after etching to expose the common thread.
    • (E) Expected volumetric displacement of the micro-wire bundles as a function of the wire-to-wire distance, determined by the wire size and the thickness sacrificial coating.
    • (F) The distal end of a 600 bundle 7.5 μm W wires covered with 1 μm glass after etching (G and H). The distal end can be precisely shaped to simultaneously access different depths in the tissue.

Compatibility with different imaging chips and tests on a retina and on a motor cortex

Tests with different imaging matrices

The process described is very flexible and agnostic as to the identity of the chip; the authors successfully interface with the imaging matrix chip of a Xenics Cheetah camera, with an organic light emitting diode display chip from Olightek and with a multi-electrode matrix device.

Retinal tests

To test the ability of the completed device to record neural activity on a flat surface, the authors used an ex vivo preparation of rat retina. A dialysis membrane held a small piece of isolated retina against the bundle in an infusion chamber, then a 138-thread bundle was lowered into contact with the retina. The recorded spikes exhibited typical unit signatures, i.e. a detected action potential located on a wire with smaller peaks on the adjacent wires. These retinal recordings demonstrate the system's ability to record individual units at high data acquisition rates and a high signal-to-noise ratio.

Test on a motor cortex

Next, the researchers tested whether it was possible to record neural activity in the deep cortical and subcortical areas across a large spatial region in rodents in vivo. The recordings were made within 2 hours of implantation of the bundle into deep layers of the motor and somatosensory cortexes and of the dorsal striatum. The mice were allowed to run on a spherical treadmill, in a state of head restraint during the recording. Neural activity was easily observed in most of the wires in the bundle through a horizontal layer. Approximately 100 to more than 200 putative neurons were reliably identified over a large horizontally extended area in each recording during a typical 5-minute recording session.

enter image description here

Conclusion

Conventional two-photon imaging is generally limited in time and space, so bundles of micro-wires coupled to CMOS arrays can simultaneously record the activity of hundreds of neurons. In addition, the flexibility along the length of the distal end of the beam allows precise recordings from normally inaccessible areas, such as the striatum.

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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.

What is event-based surveillance?
The goal of event-based surveillance is to detect unusual events that might signal an outbreak. Event-based public health surveillance looks at reports, stories, rumors, and other information about health events that could be a serious risk to public health.

enter image description here

Main categories of event-based surveillance There are basically two main categories of event-based surveillance.

• Such information is unstructured. Information obtained through event-based surveillance can come from sources like reports in the media or rumors on an internet blog.

• In contrast Indicator-based public health surveillance is a more traditional way of reporting diseases to public health officials. Indicator-based surveillance involves reports of specific diseases from health care providers to public health officials. Such information may be described as structured information because the information obtained is standardized.

Examples of event-based health surveillance: WHO’s global surveillance system picks up public health threats 24 hours a day, 365 days a year. Once an event is verified, WHO assesses the level of risk and sounds the alarm. Within 48 hours of an emergency, WHO grades the severity of the event, activates the incident management system and deploys field teams.

Design of EventEpi at The Information Centre for International Health Protection. Reading the articles, discussing their relevance, and putting key information into a database is a time-consuming process. The Information Centre for International Health Protection (Informationsstelle für Internationalen Gesundheitsschutz, INIG) at RKI, performs event-based surveillance to identify events relevant to public health in Germany. Their routine tasks include reading online articles from a defined set of sources, evaluating them for relevance, and then manually filling a spreadsheet with information from the relevant articles. This spreadsheet is called Ereignisdatenbank (IDB). enter image description here

To support event-based surveillance, but also to gain insights into what makes an article and the event it describes relevant, the authors of “EventEpi–A Natural Language Processing Framework for Event-Based Surveillancedeveloped a natural-language-processing framework for automated information extraction and relevance scoring.

Their approach consists of two complementary parts: key information extraction and relevance scoring. Both approaches are integrated in a web application called EventEpi. With the exception of the convolutional neural network for which they used Keras, they used the Python package scikit-learn to implement the machine learning algorithms.

The IDB has to be preprocessed before any application of NLP. was not designed to be used with machine learning algorithms. It thus contained some inconsistencies that might not disturb human users but had to be resolved before machine processing. For example a case count could contain numerals as strings instead of numerical digits. Other entries have inconsistent naming schemes. In addition entries in the IDB were written in German but the output of EpiTator has to be in English.

The authors performed named entity recognition in two steps:

  • EpiTator, an open-source epidemiological annotation tool, scraped relevant sources and suggested many different candidates for the following entities: disease, country, date, and confirmed-case count. To accomplish the key information extraction, two problems needed to be solved:
    • First, the output of EpiTator needed to be comparable to the entries in the IDB.
    • Second and more importantly, the output of EpiTator needed to be filtered. A naive approach to finding the key entity out of all the entities returned by EpiTator is to pick the most frequent one. This approach worked well for detecting the key country and disease, but not for the key date and confirmed-case count. For those, the authors developed a learning-based approach.
  • The second part of developing a framework to support EBS was to estimate the relevance of epidemiological articles. The scientists framed the relevance evaluation as a classification problem. They trained a naive Bayes classifier to find the most likely entities in that set. For relevance scoring, the authors defined two classes to which any article might belong:
    • The article is relevant if it is in the event-based surveillance database.
    • Irrelevant otherwise.

Two sources stood out as being relevant, and easy to scrape:

  • World Health Organization Disease Outbreak News (WHO DON)
  • ProMED Mail.

The authors compared the performance of different classifiers, using document and word embeddings. State-of-the-art text classifiers tend to use word embeddings for vectorization rather than the tf-idf and bag-of-words approach. Word embeddings are vector representations of words that are learned on large amounts of texts in an unsupervised-manner. Proximity in the word embedding space tends to correspond to semantic similarity. The researchers compared six different classifiers for the relevance scoring task. Two of the tested algorithms stood out:

  • The multilayer perceptron performed best overall.
  • The support-vector machine, on the other hand, had the highest recall (0.88) which can be of higher interest for epidemiologists.

Finally, the authors integrated these functionalities into a web application called EventEpi where relevant sources are automatically analyzed and put into a database. The same fundamental issues encountered in using machine learning in general apply here as well, in particular bias and explainability.

Tackling individual biases and personal preferences during labeling by experts is essential. It will also be important to show why EventEpi extracted certain information or computed a relevance, for it to be adopted but also critically assessed by epidemiologists for improvement.

At the moment EventEpi only presents results to the user. However it could be expanded to be a general interface to an event database and allow epidemiologists to note which articles were indeed relevant as well as correct key information, an approach called active-learning

The overall framework, can be used in production, promising improvements in event-based surveillance. The source code is publicly available at https://github.com/aauss/EventEpi

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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.

Bats, although mammals, are not phylogenetically very close to humans, so we would not expect them to harbor many harmful viruses to our species.

enter image description here Source: Вых Пыхманн via Wikipedia

The order of bats contains more than 1,200 species. Because of this genetic diversity, information about one species may not apply to other species. In recent years, however, it has emerged that viruses have spread from bats to other mammals. For example, serological evidence and detection of viruses linked to ebolaviruses in bats suggest that bats are indeed one of the reservoirs of the virus.

However, although bats harbor many different viruses, their spread to other animals is extremely rare. One reason is that for such an event to occur, several factors should be conducive to transmission.

The ability of bats to host many viruses without showing pathology suggests that bats have developed immune mechanisms different from those of other mammals. This tolerance to viruses goes hand in hand with reduced inflammation.To explain this singular characteristic, it is necessary to compare it with another singular characteristic of bats: It is a mammal with the capacity to fly.

The metabolic rate of bats in flight is double that of running rodents of similar size. The increased metabolic rate that accompanies the flight would result in higher levels of oxygen-free radicals. To mount an immune response to the damage caused by this high metabolism, would be energetically expensive.

Bats have therefore developed mechanisms leading to reduced inflammation. It would also explain why bats of some species live longer than expected given their high metabolism and small size. Some bats can live up to 40 years, while a rodent of the same size can live only two years.

Small animals with a fast heart rate and metabolism generally have a shorter lifespan than larger animals with a slower heartbeat and a slower metabolism. But bats are unique because they have a much longer lifespan than other mammals of the same size.

But a reduced inflammatory response enables rapid replication of viruses, especially in stressful conditions that affect the immune system.

  • The awakening of hibernation is a stressful event for bats. Many large brown bats are latently infected and Gerowet and his colleagues have shown that the virus reactivates when it comes out of hibernation. This reactivation is also associated with a low level of antibodies to the virus. After hibernation, antibody levels rise, which puts the virus back to latency.

  • The virus also reactivates when bats are infected with a bacterial or fungal infection. Small brown bats are particularly susceptible to an often fatal fungal infection known as white nose syndrome. A study examining the effects of stress induced by this infection showed that bats infected with fungi had 60 times more coronavirus in their intestines than uninfected bats. The specific protection mechanisms of these bats results in a rapid response that blocks the virus outside the cells. Indeed, paradoxically a host that tolerates well the presence of viruses, because it controls inflammation, allows viruses to increase their rate of replication, by genetic selection, without damaging their host.

  • Disturbances in bat habitat also seem to stress these animals and cause them to spread even more viruses in their saliva, urine and feces which can infect other animals. "Increased environmental threats to bats can add to the threat of zoonosis," said Brook, who is also working with a Madagascar-based field project that explores the link between loss of bat habitat and spread of bat viruses to other animals and humans.

Such rapidly reproducing viruses generate extreme virulence when overflowing to hosts that do not have the same immune capabilities as bats.

When these virulent viruses travel from bats to animals without a rapid response immune system, they quickly overwhelm their new hosts.

Brook and Boots are developing a more formal model of disease progression in bats to better understand the spread of the virus to other animals and humans.

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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.

A scientist from the Universitätsklinikum Erlangen, Heiko Bruns, pursues an innovative hypothesis on cancer metastases. He wrote his doctoral thesis on tuberculosis bacteria hidding in macrophages, and his postdoctoral thesis focused on the importance of macrophages in the context of cancer metastasis.

Macrophages are a type of white blood cell, which gobbles up and digests cell debris, foreign substances, microbes and cancer cells. Macrophages enter damaged tissues by the endothelium of blood vessels, a process known as extravasation. This process is very similar to what is currently thought to be the metastasis process.

enter image description here Classical conception of the metastasis process Source: doi: 10.1038 / nri3789

It is well known that macrophages can contribute to the growth and progression of cancers. Macrophages can also positively and negatively influence the results of anti-cancer treatments. Unfortunately some pathogens managed to lives inside those powerful macrophages. This allows them to escape from the immune system. This is the case with Mycobacterium tuberculosis or HIV.

Metastases are responsible for most of the deaths caused by cancer. Dr. Bruns believes that it is currently unclear how metastases form. So far, it has been assumed that they spread throughout the body via the lymphatic vessels and the bloodstream. But this mechanistic hypothesis cannot explain why some organs are preferably targeted in metastasis while other are relatively preserved. This was first discussed as the "seed and soil" theory by Stephen Paget in 1889. enter image description here Source Mikael Häggström via Wikipedia

Paradoxically, cancer patients with a high number of macrophages have a reduced life expectancy. In a mouse model, tumor growth almost stops when the macrophages where removed.

Heiko Bruns assumes that individual tumor cells are consumed by phagocytes, but are not necessarily eliminated by them. Instead, he suspects that tumor cells are using macrophages as "Trojans horses". They could thus escape detection and travel through the body to colonize other organs.

Dr. Heiko Bruns' idea was accepted into the 'Experiment! In search of bold research ideas' based on this unusual question. This idea received funding of 120,000 euros from the Volkswagen Foundation until the end of 2021.

It has long been assumed that lifespan and health are strongly correlated, but although there has been an overall increase in human life expectancy in recent decades, it is too often accompanied by deterioration of health.

A new study published on February 26 in Nature shows the influence of two epigenetic regulators on aging. Scientists led by Jie Yuan from the Chinese Academy of Sciences in Shanghai have studied the BAZ-2 and SET-6 proteins in Caenorhabditis elegans worms, which are orthologs of the human proteins BAZ2B and EHMT1.

Through genome-wide RNA-interference-based screening of genes that regulate behavioral deterioration in aging C. elegans, the researchers identified 59 genes as potential health modulators during aging. Essentially the proteins expressed by these genes, read and write epigenetic signals.

Among these modulators, they found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone SET-6, accelerate the deterioration of the behavior of C. elegans by reducing the mitochondrial function, and repressing the expression of the encoded mitochondrial proteins. in the cell nucleus.

The researchers found that the levels of the two proteins increase with age in C. elegans and mice, which in turn attenuates the expression of genes involved in mitochondrial function.

BAZ-2 and SET-6 are complementary epigenetic mechanisms. SET-6 is an "epigenetic writer" and BAZ-2 is an "epigenetic reader" which recognizes modified histones and recruits transcriptional regulators.

Histones are proteins located in the nucleus of eukaryotic cells. They are the main protein components of chromosomes. They are closely associated with DNA and allow their compaction, but they also modify the expression of proteins by various epigenetic mechanisms known as the "histone code".

enter image description here Source Wikipedia.

How do BAZ-2 and SET-6 accelerate aging? The researchers found that the two proteins bind together to the promoter regions of more than 2,000 genes, and decrease their expression via methylation of histones. Among these target genes are many mitochondrial genes encoded nuclear. By suppressing the expression of these genes, BAZ-2 and SET-6 reduce oxygen consumption and ATP production, and decrease the critical stress responses that maintain mitochondrial proteostasis. The resulting metabolic slowdown discourages the worms from assimilating their food and they mate less.

This mechanism is conserved in the neurons of cultured mice and human cells. What about the orthologs of these epigenetic proteins in humans? A review of the databases shows that expression by human orthologs of the two proteins mentioned above, BAZ2B and EHMT1, increases with age and is positively correlated with the progression of Alzheimer's disease. Researchers have verified that ablation of BAZ-2 mouse ortholog Baz2b attenuates age-dependent body weight gain and prevents cognitive decline in aging mice.

enter image description here While wild-type mice grew fat with age, animals lacking both copies of the epigenetic reader Baz2b stayed trim, indicating improved mitochondrial function. [Yuan et al., Nature, 2020.]

However, it must be asked whether BAZ-2 and SET-6 would rather mediate age-related physiological adaptation, rather than the agents of aging itself. Indeed their action could reflect a mechanism of adaptation to a progressively more hostile biological environment.

Post Intensive Care Syndrome (PICS) describes a set of disorders that are common in patients with severe illness and / or intensive care. Since the majority of the literature in intensive care medicine focuses on short-term outcomes (for example, survival), understanding of the patient's long-term development is relatively limited, since the latter is then considered to be healed.

Cognitive impairment includes deficits in memory, attention, speed of mental processing and problem solving. These impairments affect up to 80% of people who have experienced a serious illness. Most patients' symptoms improve or even disappear completely within the first year after treatment in the intensive care unit.

The underlying pathophysiology of cognitive impairment in critical care survivors is not well understood, but prolonged inflammation can play an important role

High Mobility Group Box 1 (HMGB1), a protein released in tissue damage and during severe inflammation, has been shown in laboratory animals to remain in high concentration long after the trauma and can cause inflammation hippocampal and cognitive impairment. enter image description here Source: Life Science Databases(LSDB) via Wikipedia.

Humans and other mammals have two seahorses, one on each side of the brain. The hippocampus is part of the limbic system. In Alzheimer's disease, the hippocampus is one of the first areas of the brain to be damaged; short-term memory loss and disorientation are among the first symptoms. People with extensive bilateral hippocampal lesions may suffer from anterograde amnesia: the inability to form and retain new memories.

The form of neural plasticity known as long-term potentiation (LTP) was originally discovered in the hippocampus and has often been studied in this structure. LTP is considered to be one of the main neural mechanisms by which memories are stored in the brain.

Anti-HMGB1 treatment given several days after a serious illness can reduce cognitive decline in mice

Researchers at the Karolinska Institutet in Sweden conducted a 6-month prospective follow-up study of HMGB1 plasma levels and cognitive function in survivors of intensive care (clinical trial NCT02914756). 917 patients admitted to intensive care were screened, of which 100 patients were included in the clinical trial, and they were subjected to cognitive function tests and to the measurement of plasma levels of HMGB1 at 3 and 6 months after discharge

The observations were made in these patients show a significant elevation of HMGB1 plasma at 3 and 6 months after discharge, and is associated with cognitive dysfunction.

The cellular source of this systemic HMGB1 is unknown, but it should be noted that HMGB1 is usually secreted by immune cells (such as macrophages, monocytes and dendritic cells) as a mediator of the cytokines of inflammation.

Given these well-established pro-inflammatory properties of extracellular HMGB1, this suggests continued inflammation without resolution of the inflammation. In light of the experimental results on the attenuation of cognitive dysfunction in laboratory animals by anti-HMGB1 therapy, it is tempting to ask whether blocking the pro-inflammatory activity of HMGB1 in ICU survivors could improve cognitive outcomes.

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.

enter image description here

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.

enter image description here

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.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases characterized by the presence of neuropathological aggregates of phosphorylated TDP-43. The TDP-43 protein is also a component of stress granules. Stress granules are cytoplasmic vesicles that form when a cell experiences intense stress conditions. Under these conditions the cell considerably reduces its production of proteins.

So almost all of the studies aiming at reproducing TDP-43 inclusions have been carried out under conditions of intense short-term stress, which differ significantly from the chronic stress conditions occurring in neurodegeneration.

In addition, most of the studies have been done using immortalized cell lines, which are very different from natural cells.

In the article which is the subject of this post and which was posted on the pre-print server BioRxiv, the authors show that a state of mild but prolonged oxidative stress, leads to the formation of stress granules in primary fibroblasts and neurons derived from iPSC in both controls and ALS patients.

In their experiment, primary fibroblasts and neurons derived from induced pluripotent stem cells from ALS patients carrying mutations in the TARDBP (n = 3) and C9ORF72 (n = 3) genes and healthy controls (n = 3) were exposed to oxidative stress by sodium arsenite.

The formation of stress granules and the cellular response to stress were evaluated and quantified by immunofluorescence and electron microscopy analyzes. The scientists found that not only an acute, but also a chronic oxidative insult, is capable of inducing the formation of stress granules in primary fibroblasts and neurons derived from iPSC.

The researchers assume that, when stress is chronic, as in neurodegeneration, cells carrying a TARDBP mutation show less capacity to induce a long-term protective mechanism, unlike C9ORF72 mutant cells.

Above all, the authors of the article observed the recruitment of TDP-43 in stress granules and the formation of phosphorylated aggregates of TDP-43, very similar to the abnormal inclusions observed in the autoptic ALS / FTD brains, this only in case of chronic stress. In addition, in fibroblasts, the cellular response to stress was different in control compared to mutant ALS cells, probably due to their different vulnerability.

A quantitative analysis also revealed differences in terms of the number of cells forming stress granules and the size of stress granules, suggesting a different composition of the vesicles in acute and chronic stress.

In prolonged stress, the stress granules and the formation of phosphorylated TDP-43 aggregates were concomitant with an increase in p62 and deregulation of autophagy in ALS fibroblasts and iPSC-derived neurons. This alteration in autophagy suggests that prolonged stress alters the cellular mechanism of protein degradation and reduces the ability of stress granules to disassemble properly.

The authors of the article assume that in neurodegeneration, there is a critical stress threshold above which the disassembly of stress granules becomes impossible and causes the quality control of system proteins, including chaperones, to be engulfed, and the autophagic and ubiquitin / proteasome systems.

Cells derived from ALS patients, exposed to persistent oxidative stress, represent an appropriate bioassay to study not only the pathology of TDP-43, but also to test potential drugs capable of preventing or breaking down phosphorylated inclusions of TDP-43 .

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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.

For anyone studying research against neurodegenerative diseases, it is striking to note the large number of studies which each claim to have identified a key element, different in each study, and which would be a causative factor of the disease. In addition, many studies are contradictory with each other.

In epidemiology, Mendelian randomization is a method of using measured gene variation, known to express the causal effect of exposure to a disease in observational studies, without the need for a traditional randomized clinical trial. Even better, it allows us to escape traditional biases in epidemiological studies, such as reverse causation and confusion. This method was first proposed in 1986 by Gray and Wheatley.

Since genotypes are randomly assigned when passed from parents to offspring during meiosis, the distribution of the population genotype should not be linked to the confounding factors that generally affect observational epidemiological studies. In this regard, Mendelian randomization can be viewed as a randomized controlled trial.

Because polymorphism is the instrument, Mendelian randomization depends on previous genetic association studies that have provided good candidate genes for the response to risk exposure.

Each of these selected genetic variants must satisfy three conditions, relevance, independence, exclusion restriction.

Among the various genetic and environmental factors that have been identified to be associated with ALS, the association between blood lipid metabolites and ALS has recently received considerable attention. The associations between lipids and ALS are strong and comparable in strength to many risk factors for ALS previously identified.

ALS patients suffer from increased energy expenditure at rest and from weight loss. Previous observational studies have shown that ALS patients frequently experience dyslipidemia. Dyslipidemia is characterized by abnormal levels of high density lipoproteins (HDL), low density lipoproteins (LDL), total cholesterol (TC) and triglycerides (TG).

The positive association between dyslipidemia and ALS suggests that elevated levels of non-HDL lipids may play a protective role in the progression of ALS. Consistent with observational studies in humans, research with ALS mouse models has also shown that the overall survival of ALS mice is reduced under calorie restriction. However, the relationship between dyslipidemia and ALS is also controversial, conflicting results have been reported for basal serum lipid levels, the cause of dyslipidemia, and the relationship between serum lipid levels and the progression of ALS disease.

For example, many observational studies following ALS have found no association between dyslipidemia and ALS. In addition, some studies have shown that patients with ALS often suffer from hypolipidemia - which is mainly characterized by low levels of LDL - in men and women with ALS. The association between hypolipidemia and ALS is further confirmed in a mouse ALS model. The conflicting results on the relationship between lipid levels and ALS may be due in part to the relatively small sample sizes used in previous studies and in part to uncontrolled confounders that are inevitable in observational studies .

Determining the causal impact of lipids on ALS is difficult using traditional randomized controlled trial studies because these studies necessarily require long-term follow-up, are expensive and often unethical. Therefore, it is desirable to determine the causal relationship between lipids and ALS through observational studies. Mendelian randomization is a powerful statistical tool for examining the causal relationship and estimating causal effects in observational studies.

Scientists have studied the causal effects of four blood lipid traits on the risk of ALS:

  • high density lipoprotein,
  • low density lipoprotein (LDL),
  • total cholesterol,
  • triglycerides.

The authors first selected SNPs (genetic variants) which can serve as valid instrumental variables for each of the four lipid traits (HDL, LDL, TC and TG).

Taking advantage of the instrument variables from several large-scale association studies on the genome in European and Asian populations, the authors performed one of the most important and comprehensive Mendelian randomization analyzes to date on the causal relationship between lipids and ALS. Among the four lipids, they found that only LDL is causally associated with ALS and that a higher level of LDL increases the risk of ALS in European and East Asian populations.

The large sample size used in this study allows the authors to fully establish a positive causal effect of the modifiable factor LDL on ALS in European and East Asian populations. The inferred causal relationship between LDL and ALS is robust in the choice of statistical methods and is carefully validated by various sensitivity analyzes.

The positive causal effect of LDL on ALS suggests that future development of strategies to reduce LDL levels would likely reduce the burden of ALS. LDL is a modifiable risk factor, the levels of which can be reduced by various intervention strategies. For example, dietary changes such as increased fiber intake, increased phytosterol consumption, and increased consumption of nuts can all lead to a reduction in LDL levels.

Restrictions on dietary cholesterol, restrictions on high-carbohydrate diets, and restrictions on the consumption of trans fats can also lower LDL levels. In addition to lifestyle and dietary changes, LDL reduction can be achieved by drug therapy.

This is not a breakthrough regarding the mechanism of onset of the disease, but it introduces a tool for managing this disease.

The future development of LDL reduction strategies and the development of public policies to promote such strategies are likely to reduce the burden of ALS in society.

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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.

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