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In vivo genome editing using novel AAV-PHP variants rescues motor function deficits and extends survival in a SOD1-ALS mouse model.

- Posted in In vivo genome editing using novel AAV-PHP variants rescues motor function deficits and extends survival in a SOD1-ALS mouse model. by English by

I dislike publishing about CRISPR technology or about ALS mice models yet the results in this article, if replicated, are amazing. It means that for 5% of ALS patients, there is an hope that a future drug might extend their survival by more than 12 years!

Although CRISPR-based gene-editing technology has received unreasonable hype, it represents a promising approach to providing genetic therapies for inherited disorders, including amyotrophic lateral sclerosis.

Toxic gain-of-function superoxide dismutase 1 (SOD1) mutations are responsible for approximatively 20% of familial Amyotrophic Lateral Sclerosis cases. This means 5% of all ALS cases.

Current clinical strategies to treat SOD1-Amyotrophic Lateral Sclerosis are designed to lower SOD1 levels, notably throught the use of ASOs. On October 17, 2021, a presentation of the phase 3 VALOR study indicating that Biogen's Tofersen did not demonstrate statistical significance in the primary measure of disease progression.

On June 3, 2022, additional 12-month open label extension data was presented, demonstrating a some positive effect for participants who received Tofersen early in their disease.

In this new publication, authors from Biogen used an AAV-gene therapy to deliver CRISPR guide RNAs designed to disrupt the human SOD1 transgene in SOD1 mice (huSOD1). Those transgenic mice express the human SOD1 gene, not the murine gene, so their disease is closer to the human disease than in other SOD1 mice models.

This intrathecal injection into neonatal huSOD1 mice caused robust and sustained mutant huSOD1 protein reduction in the cortex and spinal cord, and restored motor function.

Neonatal treatment also reduced spinal motor neuron loss, denervation at neuromuscular junction and muscle atrophy, diminished axonal damage and preserved compound muscle action potential throughout the lifespan of treated mice. SOD1 treated mice achieved significant disease-free survival, extending lifespan by more than 110 days. 110 days for a mice that can live 2 years is equivalent to 12 years for humans!

Yet this is not realistic for human patients, as even if we can detect patients at risk at neonatal stage, most of them will not develop ALS, and furthermore reducing their SOD1 level means they will be susceptible to the very diseases that this therapy tries to attenuate.

Importantly, a one-time intrathecal or intravenous injection of this therapy, immediately before symptom onset, also extended lifespan by at least 170 days.

The authors' approach also uncovered key parameters that resulted in improved efficacy compared to similar approaches and can also serve to accelerate drug target validation.

One question I have is why these technologies are not used to convert the mutated SOD1 gene into the normal wild-type SOD1 gene. This is important because living with reduced levels of SOD1 puts the patient at risk for neurodegeneration!

Let's hope this will lead to a full drug development program at Biogen. Yet there will be internal competition with the team in charge of Torfersen.

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The common marmoset in biomedical research: experimental disease models and veterinary management.

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Mouse models of neurodegenerative diseases have proven inadequate in translation into clinical research. There are several reasons, one of them is that in these animals the diseases progress at an extreme speed and the other is that mice and primates have quite different nervous systems. For example, in some cases, higher primates have direct connections between upper and lower motor neurons, whereas mice always have interneurons between upper and lower motor neurons. enter image description here Source: Xocolatl via Wikipedia

The common marmoset, Callithrix jacchus, is increasingly being used as the preferred nonhuman primate model in biomedical research. Marmosets share several physiological and biological similarities with humans, and their use in research programs advances knowledge of several fields.

Mice diseases models are highly unrealistic, when transposed to humans it would mean that degeneration would appear at 20 years old! Due to the relatively shorter life span of 15 to 16 years and the smaller body size, studies conducted in marmosets may be more realistic. Since neurodegeneration is prevalent in aging humans, there has been much interest in the neurodegeneration of aging marmosets.

Their unique characteristics, such as small size, high fecundity, and rapid growth, offer additional advances in laboratory settings. This article reviews the developments in experimental disease models using marmosets based on authors' experience at the Central Institute for Experimental Animals in Japan.

The development of genetically modified marmoset models using advanced genome editing technology attracts researchers, particularly in neuroscience-related fields. In parallel, various marmoset models of human diseases induced by surgery or drug administration have contributed to preclinical and translational studies.

Among these are models:

  • for Parkinson's disease, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;
  • spinal cord injury models;
  • a model for type 1 diabetes, induced by the combination of partial pancreatectomy and streptozotocin administration;
  • a hepatic fibrosis model induced by thioacetamides.

The development of these models has been supported by refinements in veterinary care, such as the careful design of anesthetic protocols and better understanding of pathogenic microorganisms. In the second part of this review, the authors present a compilation of practices currently in use at at the Central Institute for Experimental Animals that provide optimal animal care and enable safe experimentation.

Indeed, most researchers will be reluctant to use marmosets. Diseases of mice models appear within a month, so the cost is low. No university lab would spend years before the results are available. If only for one thing, it would considerably slow down the pace of publications that condition the careers of scientists.

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Unsupervised mobile app-based cognitive testing in a population-based study of older adults born 1944.

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Trends in digitalization suggest that older adults are increasingly familiar and comfortable with new technologies, and surveys from 2019 indicate that 77% of North Americans aged 50+ own a smartphone. In Sweden 66% of Sweden's older adults born during the 1940s use the Internet daily.

Mobile app-based tools have the potential to yield rapid, cost-effective, and sensitive measures for detecting dementia-related cognitive impairment in clinical and research settings. At the same time, there is a substantial need to validate these tools in real-life settings. The primary aim of this study was thus to evaluate the feasibility, validity, and reliability of mobile app-based tasks for assessing cognitive function in a population-based sample of older adults.

The authors of a new study employed two mobile app-based cognitive tasks building on recent findings on the functional brain architecture of episodic memory and the spatiotemporal progression of AD pathology. - First, the Mnemonic Discrimination Task for Objects and Scenes (MDT-OS), taxing pattern separation as a short-term memory task. Pattern separation is the process of discriminating among highly similar but unique pieces of information (e.g., where you parked your car today vs. yesterday).

  • Second, the Object-In-Room Recall Task (ORR-LDR) was developed to tax pattern completion (29), i.e., the ability to retrieve a stored memory based on a cue of incomplete information. The ORR-LDR was implemented as a one- to three-day long-term delayed recall task, consequently assessing long-term memory.

A total of 172 non-demented older participants completed two mobile app-based memory tasks-the Mnemonic Discrimination Task for Objects and Scenes and the long-term delayed Object-In-Room Recall Task. To determine the validity of the tasks for measuring relevant cognitive functions in this population, the authors assessed relationships with conventional cognitive tests. In addition, psychometric properties, including test-retest reliability, and the participants' self-rated experience with mobile app-based cognitive tasks were assessed.

MDT-OS and ORR-LDR were weakly-to-moderately correlated with the Preclinical Alzheimer's Cognitive Composite and with several other measures of episodic memory, processing speed, and executive function. Test-retest reliability was poor-to-moderate for one single session but improved to moderate-to-good when using the average of two sessions.

The scientists observed no significant floor or ceiling effects nor effects of education or gender on task performance. Contextual factors such as distractions and screen size did not significantly affect task performance. Most participants deemed the tasks interesting, but many rated them as highly challenging. While several participants reported distractions during tasks, most could concentrate well.

However, there were difficulties in completing delayed recall tasks on time in this unsupervised and remote setting.

The authors' study proves the feasibility of mobile app-based cognitive assessments in a community sample of older adults, demonstrating its validity in relation to conventional cognitive measures and its reliability for repeated measurements over time. To further strengthen study adherence, future studies should implement additional measures to improve task completion on time.

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Synthesis of Andrographolide Triazolyl Glycoconjugates for the Treatment of Alzheimer's Disease.

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Andrographis paniculata, commonly known as creat or green chiretta, is an annual herbaceous plant widely cultivated in Southern and Southeastern Asia, where it has been believed to be a treatment for bacterial infections and some diseases. Andrographolide is the major constituent extracted from the leaves of the plant enter image description here Source: J.M.Garg - Own work, via Wikipedia

Andrographolide is a labdane diterpenoid that has been isolated from the stem and leaves of Andrographis paniculata. Andrographolide is an extremely bitter substance.

Andrographolide has been studied for its effects on Alzheimer's Disease, Parkinson's disease, multiple sclerosis and stroke.

A new andrographolide-based terminal alkyne was synthesized in good yield from andrographolide by India's scientists. Andrographolide was obtained from a natural compound andrographolide , which in turn was isolated from the leaves of the plant .

Copper-catalyzed azide-alkyne cycloaddition reaction of alkyne with -sugars furnished a library of andrographolide-fastened triazolyl glycoconjugates in good yields. The structures of these semisynthetic andrographolide derivatives were established by Fourier transform infrared, NMR, and mass spectroscopy. enter image description here The compounds were further evaluated against Alzheimer's disease using a scopolamine-induced memory impairment mice model. It was observed that antioxidant and anticholinesterase properties of these compounds contribute significantly toward their remarkable potential to improve cognitive functioning.

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Effects of trihexyphenidyl on prefrontal executive function and spontaneous neural activity in patients with tremor-dominant Parkinson's disease: An fNIRS study.

- Posted in Effects of trihexyphenidyl on prefrontal executive function and spontaneous neural activity in patients with tremor-dominant Parkinson's disease: An fNIRS study. by English by

Trihexyphenidyl (marketed as Artane and others) is an antispasmodic drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the antimuscarinic class and is often used in management of Parkinson's disease. It was approved by the FDA for the treatment of Parkinson's in the US in 2003.

Artane has been shown to have several sides effects, some similar to Parkinson's symptoms, in particular people who are older or who have psychiatric conditions may become confused or develop delirium.

Despite growing concerns about Trihexyphenidyl causing cognitive decline in tremor-dominant Parkinson disease patients, the underlying neural correlates remain unclear. Therefore, the authors investigated the effects of this drug on prefrontal executive function and spontaneous neural activity in patients with tremor-dominant Parkinson disease by utilizing functional near-infrared spectroscopy.

The authors recruited 30 patients with tremor-dominant Parkinson disease, including 15 patients receiving the treatment and 15 patients not receiving Trihexyphenidyl.

The researchers performed comprehensive neuropsychological and clinical assessments to evaluate each patient's cognitive function, mental status, and clinical symptoms.

They measured brain activation elicited from the verbal fluency task and changes in amplitude of low-frequency fluctuations at rest to investigate executive function and spontaneous neural activity, respectively. In addition, the authors examined the relationship between altered activation during task and resting state and neuropsychological and clinical data.

Compared with tremor-dominant Parkinson disease patients not taking Trihexyphenidyl, tremor-dominant Parkinson disease patients taking the treatment showed no differences on neuropsychological tests.

However, there was insufficient activity of the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, and the orbitofrontal cortex related to the frontoparietal network at rest.

Furthermore, functional near-infrared spectroscopy results were positively correlated with scores of multiple cognitive domain functions.

These findings suggest that Trihexyphenidyl treatment may lead to prefrontal dysfunction in tremor-dominant Parkinson disease patients, attenuating brain activation in executive function and cognition-related spontaneous neural activity.

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Acting on the diet or the microbiome can help relieve the symptoms of Parkinson's disease.

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Patients have long said that diets can relieve symptoms of diseases such as Alzheimer's and Parkinson's. Many ALS patients take supplements in varying amounts and types. These claims have long been derided by scientists, yet scientists are now starting to change their minds.

The authors of a new scientific article therefore investigated whether a high fiber diet influences microglial function in mouse models of Parkinson's disease that overexpress α-synuclein. These mice are called ASO (α-synuclein overexpressing) mice.

Parkinson's disease is a disease characterized by α-synuclein pathology and/or dopamine deficiency resulting from degeneration of the substantia nigra (a region of the midbrain).

Although Parkinson's disease is primarily classified as a brain disorder, 70-80% of patients experience gastrointestinal symptoms, primarily constipation, but also abdominal pain and increased intestinal permeability which usually manifest in prodromal stages (Forsyth et al. 2011; Yang et al 2019).

Braak postulated nearly 20 years ago that α-synuclein aggregation can begin in the gastrointestinal tract or olfactory bulb, and eventually reach the brainstem, substantia nigra, and neocortex via the vagus nerve ( Braak et al. 2003). A growing body of evidence supports the potential for gut-to-brain spread of α-synuclein pathology in rodents (S. Kim et al. 2019; B. Liu et al. 2017; Svensson et al. 2015).

The vagus nerve, a long winding nerve, is a major two-way information signaling pathway between the gut and the brain. Vagotomy is the surgical section of the pneumogastric nerve, or vagus nerve, at the level of the abdomen. Vagotomy has been used for decades and most patients who have had such surgery and are still alive are now elderly. A Swedish registry study investigated the risk of Parkinson's disease in patients who underwent vagotomy and hypothesized that truncal vagotomy is associated with a protective effect.

The scientists found that the risk of Parkinson's disease was indeed reduced in patients who underwent a complete truncal vagotomy, whereas there was no risk reduction in those who underwent a selective vagotomy. The risk of Parkinson's disease is also reduced after truncal vagotomy compared to the general population. These epidemiological findings are important and support the hypothesis that Parkinson's disease begins in the gut and not initially in the brain. This provides further evidence for the involvement of the vagus nerve in disease development.

Many important chemical compounds (nowadays we say "molecular" to make it sound important) are produced in the intestine and end up in the brain via the bloodstream. Many of them are made or have their production regulated by gut microbes.

These include short chain fatty acids tryptophan, leptin and ghrelin. Short chain fatty acids include butyrate, propionate and acetate. Butyrate is a known inhibitor of histone deacetylases (HDACs) and in doing so acts as an epigenetic regulator. Cytokines, key immune-regulating molecules produced in the gut, can travel through the bloodstream and influence brain function, particularly in regions of the brain where the blood-brain barrier is deficient.

Among other effects, microbial food metabolites can modulate the activation of microglia, these nerve cells which are essential for the survival of neurons are implicated in Parkinson's disease. Microglia respond to signals from inside the brain, but also receive information from the periphery, including the gut microbiome (Abdel88 Haq et al. 2019). Microglia from germ-free adult mice show an immature gene expression profile and do not respond adequately to immunostimulants (Erny et al. 2015; Thion et al. 2018). However, if these germ-free mice are fed a mixture of short-chain fatty acids, microglial maturation is restored (Erny et al. 2015).

The gut microbiota is a virtual organ that produces a myriad of molecules needed by the brain and other organs. Humans and microbes are in a symbiotic relationship, humans feed the microbes, and microbes in turn provide essential molecules.

The phyla Bacteroidetes and Firmicutes represent approximately 80% of total human gut microbiota. The genera of the Firmicutes phylum include Clostridium, Lactobacillus, Bacillus, Clostridium, Enterococcus, and Ruminicoccus. The phylum Bacteroidetes mainly includes the genera Bacteroides and Prevotella.

The phylum Actinobacterium is dominated by the genus Bifidobacterium. Bifidobacteria and lactobacilli are generally considered beneficial bacteria and are frequently sold as probiotic supplements. Strains of the genus Clostridium or lipopolysaccharide taxa such as Enterobacteriaceae have been associated with disease states in many neurodegenerative diseases including ALS (Charcot's disease).

Similarly but somewhat controversially, the Firmicutes/Bacteroidetes ratio, which explores the relationship between the two dominant phyla, has been associated with various neurodegenerative pathologies.

So, the intestinal microbiome is altered in Parkinson's disease. It is found in mice models of Parkinson's disease (the mice have been genetically engineered to carry a disease resembling that of Parkinson's) that the fecal levels of short-chain fatty acids are different in mice with Parkinson's disease and mice. healthy. It is the intestinal bacteria that transform dietary fiber into short-chain fatty acids by fermentation.

The authors designed personalized high-fiber diets, each containing 20% ​​of a prebiotic blend of two or three dietary fibers designed to support the growth of 5 distinct gut bacterial taxa and stimulate the production of short-chain fatty acids based on of faecal fermentation in vitro.

The scientists then observed broad changes at the microbial phylum and genus level after administration of a prebiotic diet, displaying an increase in Bacteroidetes and a decrease in Firmicutes in mice fed a prebiotic diet, resulting in a lower Firmicutes ratio. /Bacteroidetes (F/B) that has been associated with general features of metabolic health.

Interestingly, Bacteroidetes have been shown to be reduced in Parkinson's patients compared to age-matched controls, suggesting that the prebiotic may counteract this effect (Unger et al. 2016). Additionally, they observed a decrease in proteobacteria, a phylum often increased in dysbiosis and inflammation and elevated in fecal samples from patients with Parkinson's disease (Keshavarzian et al. 2015; Shin, Whon, and Bae 2015).

A fiber-rich prebiotic diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice.

Meanwhile, the gut microbiome of ASO mice adopts a health-correlated profile upon prebiotic treatment, which also reduces microglial activation.

Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum reveals increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to their wild-type counterparts on a standard diet.

Prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of microglia's disease-associated protective macrophage (DAM) subsets. Microglia are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for development, maintenance and proliferation (Elmore et al. 2014).

To test the opposite effect: If depletion of microglia eliminated the beneficial effects of prebiotics, the authors added PLX5622 to the diet of mice aged 5 to 22 weeks and quantified the number of IBA1+ microglia in various brain regions. PLX5622 is a brain-penetrating CSF1R inhibitor that can deplete microglia with no observed effects on behavior or cognition (Elmore et al. 2014).

Depletion of microglia using a CSF1R inhibitor effectively eliminated the beneficial effects of prebiotics and restored motor deficits in ASO mice despite a prebiotic diet.

These studies reveal a novel microglia-dependent interaction between diet and motor Parkinson's disease in mice, findings that may have implications for neuroinflammation and Parkinson's disease.

Prebiotics present a potentially promising therapeutic approach, as diet contributes significantly to the composition of the microbiome and epidemiological evidence has linked high fiber diets to reduced risk of developing Parkinson's disease (Boulos et al 2019).

While increased vegetable intake and adherence to a Mediterranean diet are associated with a lower risk of Parkinson's disease, people consuming a low-fiber, highly processed Western diet have an increased risk of being diagnosed with Parkinson's disease. (Alcalay et al. 2012; Gao et al. 2007; Molsberry et al. 2020).

Several ongoing clinical trials are exploring the beneficial effects of probiotics and prebiotics on Parkinson's disease outcomes. Acting on the diet or the microbiome can help relieve the symptoms of Parkinson's disease.

A strange post by Alsnewstoday

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On the 14th November Alsnewstoday published a bizarre story about a person who supposedly healed from ALS with an unspecified regimen at Lifestyle Healing Institute.

There is no scientific publication about this case even if the post tells a scientific publication may be written in the future with Florida Gulf Coast University. Yet a quick search on Pubmed shows no publication on ALS in this small university, so FGCU may not have someone working on this disease.

Lifestyle Healing Institute is not a medical institute, it is unclear what is the scientific basis behind this "institute". They claim to have a "patended" method, yet a search in patent database does not return anything with Lifestyle Healing Institute as assignee.

It is possible there are some revert cases of ALS. I once discuss with someone who told they were able to revert the "pre-ALS" case of their father mostly by changing his diet. Another person told on a forum they reverted their case simply by becoming obese and when later they decided to thin a bit, symptoms reappeared. And many studies tell that the less dangerous BMI for ALS patients is 27, which is being overweight.

However it is a bit surprising that a patient is diagnosed with ALS if the symptoms are simply "difficulty using his hands" and change of gait. ALS is not something mild, it kills most of patients in a few years. So one can wonder if this person does not have ALS, but something closer to Parkinsonism. Despite the textbooks describing very different diseases, in real life at the beginning of the disease they might look similar. Parkinsonism has been reverted in mice through an adapted diet.

Finally it is interesting to note that ALsnewstoday is published by BioNews, Inc. As their website tells, BioNews business model is to funnel "hard to reach" patients to clinical trials or commercial organizations.

Leukocyte surface biomarkers implicate deficits of innate immunity in sporadic Alzheimer's disease.

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This is probably unimportant but who knows. 26 Scientists from Australia, China and US, wanted to find a blood-based diagnostics in sporadic Alzheimer's disease. Such a blood test would permit quick and low cost diagnosis in at-risk individuals. While they didn't discuss it explicitly, their work implies that immune system activation in Alzheimer's disease.

But let's go back to the topic of a putative blood test. Today positron emission tomography (PET) neuroimaging and cerebrospinal fluid (CSF) measurements, the most commonly used biomarkers, can yield an accurate diagnosis of Alzheimer's disease. However, this approach is not feasible as a routine screening tool in a clinical environment. Therefore, there is a critical need to develop blood-based, cost-effective screening tools to detect AD in asymptomatic patients.

While current biomarkers have conventionally focused on the central nervous system (CNS), emerging evidence have shown abnormal systemic changes in the whole body.

This is an intriguing notion, Alzheimer's disease is thought as a disease of the central nervous system, or even only of the brain. Changes in other physiological systems such as the blood circulatory system or immune systems hint at a different etiology or at least mean that we do not reallyunderstand Alzheimer's disease.

Complement control protein are proteins that interact with components of the complement system. enter image description here

The complement system consists of a number of small proteins that are synthesized by the liver, and circulate in the blood as inactive precursors. When stimulated by one of several triggers, it releases cytokines and initiates an amplifying cascade which results in stimulation of phagocytes to clear foreign and damaged material, and activation of the cell-killing membrane attack complex.

About 50 proteins and protein fragments make up the complement system, including serum proteins, and cell membrane receptors.

This study was comprised of four stages.

  • Stages I and II were exploratory and were aimed at investigating major leukocyte and CD markers. The scope of leukocyte surface antigens detected in Stage II was readjusted in Stage III. A total of 34 leukocyte antigens types were examined by flow cytometry immunophenotyping.

  • In Stage III, immune markers associated with AD risk alleles that potentially operate through immune cells, including microglia (thought to play a key role in AD pathogenesis), were included. Markers linked with newly identified changes in leukocytes that may be associated with the onset of AD were also included. These experiments resulted in the identification of three key biomarkers that together had high validity and reliability in identifying subjects presenting with preclinical or clinical AD and other brain biomarkers associated with the disease.

  • The results were validated in an independent cohort, Stage IV.

The scientists identified leukocyte markers differentially expressed in the patients with Alzheimer's disease. They propose a panel for the Alzheimer blood test that includes four leukocyte markers - CD11c, CD59, CD91, and CD163. CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts.

These biomarkers could have a major impact on clinical practice by allowing primary care physicians to identify individuals at high risk of having amyloid burden in their brains with a simple blood test. A future longitudinal study could provide information about the potential changes in these biomarkers over time as the disease progresses in a given individual.

In this article the authors do not discuss about the Alzheimer etiology, but IMO their results could reinforce the hypotheses about Alzheimer disease resulting from an infection.

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Stroke and risk of ALS

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A recent study proposes that age-related dysregulation of TDP-43 exacerbates post-stroke inflammation and ischemic damage and may contribute to neurodegenerative processes. enter image description here Stroke is a leading cause of death and the leading cause of long-term disability. Patients who survive a stroke are at greater risk of later developing vascular and/or Alzheimer-type dementia. This risk is particularly high in the elderly because various cellular processes are altered during aging.

In addition to processes associated with chronic neurodegeneration, a growing body of research suggests that dysregulation of TDP-43 neurons can occur as a result of brain injury, including single and repetitive traumatic brain injury. Researchers have recently shown that aging-associated processes significantly affect microglia activation patterns and innate immune signaling after stroke in aged female and male mice. However, how aging affects immune signaling in neurons and/or microglia/neuron crosstalk in response to ischemic injury remains unclear.

In a new paper, researchers have focused their study on transactive response (TAR) DNA-binding protein 43 (TDP-43). TDP-43 has been identified as a major constituent of ubiquitinated nuclear and cytoplasmic inclusions in fronto temporal degeneration (FTD), ALS, and Alzheimer's disease. While normally localized to the nucleus, in these diseases TDP-43 forms insoluble ubiquitinated inclusions in which it is abnormally phosphorylated and cleaved into C-terminal 35 and 25 kDa fragments lacking the N-terminal nuclear localization signal.

As previous work, notably of famous researchers like Jean-Pierre Julien, suggested that TDP-43 could serve as a modulator of inflammation, by acting as a co-activator of p65 NF-κB, these researchers hypothesized that the age-related progressive accumulation of cytoplasmic TDP-43 could trigger the activation of pathogenic NF-κB pathways, leading to dysregulation of the innate immune response and thus increasing the susceptibility of neurons to ischemic injury.

They therefore designed a study to identify and characterize age-related expression patterns of TDP-43 in neurons and microglia and to assess its role as a modulator of inflammation following ischemic injury.

The observed that accumulation of cytoplasmic TDP-43 was associated with increased microglial activation and innate immune signaling observed by in vivo bioluminescence imaging and immunofluorescence analysis. The presence of ubiquitinated TDP-43 aggregates and its cleaved TDP-35 and TDP-25 fragments was markedly increased in 12-month-old mice, which showed larger infarcts as well as increased neuronal death.

The researchers then showed that the increase and/or overexpression of cytoplasmic TDP-43 drives the NF-κB response and further increases the levels of pro-inflammatory markers and ischemic damage after stroke. Taken together, their results suggest that TDP-43 may act as a modulator of age-related inflammation after stroke.

The researchers then analyzed post-mortem brains autopsied at different times after a human stroke, hypothesizing that they would find TDP-43 immunoreactive structures located in the cytoplasm of neurons in the periphery and in the central region of the lesion. ischemic. To investigate this issue, they performed immunohistochemical analyzes of post-mortem post-stroke brain tissue autopsied 1 to 5 days after the stroke. The analysis was performed focusing on two distinct regions of the ischemic lesion, the peri-infarction and central region (cortical sections) and compared to the corresponding controls. The analysis was carried out using an anti-human TDP-43 antibody. In healthy areas, the antibody was found present in well circumscribed and positively stained nuclei, while the cytoplasmic compartment was almost completely devoid of TDP-43 immunoreactivity. In contrast, areas with TDP-43 after acute ischemic stroke revealed increased immunoreactivity in the cytoplasm and, in some cases, extending to cell processes.

The increase in cytoplasmic TDP-43 immunoreactivity was greatest at day 5 after stroke. Stroke in humans is therefore associated with increased TDP-43 immunoreactivity in the the cytoplasmic compartment.

One should note that the conclusions are not exactly the same in experiments in mice and post-mortem observation of brains. In the first case, the poorly localized aggregates of TDP-43 are an element favoring the arrival of the stroke, in the other case, it is on the contrary the arrival of the stroke which seems to create the presence of these poorly localized aggregates.

Gut microbiome and Parkinson's disease: Perspective on Pathogenesis and Treatment.

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Depending on the author, Parkinson's disease is a disease characterized by ⍺-synuclein aggregation (Lewy bodies) or by dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms.

Over the past few decades of research, there has been a vague discourse on inflammation-induced oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity as the cause of neuronal damage and loss associated with Parkinson's disease. However, this type of discourse is also present in other neurodegenerative diseases and it is not clear how it would explain the characteristics of Parkinson's disease (or of other diseases).

Recently enteric and central nervous systems have been implicated in the pathogenesis of sporadic Parkinson disease, thus highlighting the crosstalk between the gut and brain. Indeed the staging in Parkinson's disease was described by Heiko Braak in 2003. Braak and colleagues state that Parkinson's disease begins when a foreign agent enters the body via the nose or gastrointestinal system and travels into the central nervous system (CNS). The presence of Lewy bodies in the enteric and peripheral nervous systems supports their claim.

In this review, the authors summarize how the alterations in the gut microbiome can affect Parkinson disease pathogenesis.

The scientists highlight various mechanisms increasing/decreasing the risk of Parkinson disease development. Based on the previous supporting evidence, they suggest how early interventions could protect against Parkinson disease development and how controlling specific factors, including patients' diet, could modify disease's mechanisms.

The scientists explain the strong relationship between the gut microbiota and the brain in Parkinson disease subjects, by delineating the multiple mechanisms involved in neuroinflammation and oxidative stress.

They conclude that the neurodetrimental effects of western diet and the neuroprotective effects of Mediterranean diets should be further explored in humans through clinical trials.

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