A new publication by Jamie K Wong, and colleagues including two well known ALS scientists argues apolipoprotein B-100 in sporadic amyotrophic lateral sclerosis CSF is the putative agent responsible for inducing motor disability, motor neuron degeneration and pathological translocation of TDP-43.

While there are publications with similar claims about every week, this one sounds impressive, the scientists here have really worked hard to make sure they haven't left any stone unturned.

For a layperson like me, at first glance, this publication makes sense as there is a special relation between ALS and lipid metabolism. Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph. There are multiple classes of apolipoproteins and several sub-classes

ApoD level increases in nervous system with a large number of neurologic disorders inclusive of Alzheimer's disease, schizophrenia, and stroke. ApoE has been implicated in dementia and Alzheimer's disease.

So why not ApoB and ALS? Moreover overproduction of apolipoprotein B can result in lipid-induced endoplasmic reticulum stress and insulin resistance in the liver. ER stress leads to mislocalized misfolded proteins in cytosol, and half of ALS patients exhibit insulin resistance. In addition patients with ALS have higher levels of LDL-C, ApoB, and ApoB/ApoAI ratio already 20 years before diagnosis.

Yet this is not a study on humans but on mice and motor neurons in-vitro, and as usual a lot could be said about mice animal models of ALS. So maybe their claim, that ApoB is the agent responsible for inducing sporadic ALS, needs more work.

In addition a recent publication claimed that ALS patients that have elevated levels of ApoB in blood are associated with a lower risk of death. ApoB is also correlated with LDL (the "bad" cholesterol). Another study claimed the contrary. Yet another study did not find any evidence of association between lipoprotein or apolipoprotein levels and clinical findings.

There is also a lack of associations of cholesterol-lowering drugs (which lowers ApoB), antihypertensive drugs, and antidiabetics with the risk of ALS.

So we must remain cautious again, anyway even if this finding about ApoB and ALS was true, a commercial drug would be available only in 10 or 20 years.

Studies in arthropods have revealed the existence of mental maps of their position that are very effective in achieving their objective. These maps make it possible to determine their position and the direction to follow. Scientists call these maps "path integration". enter image description here Three important discoveries showed how these mental maps were implemented in the mammalian brain. * The first, in the early 1970s, is that hippocampal neurons, called place cells, respond to the position of the animal. * The second, in the early 1990s, is that neurons in neighboring regions, called head direction cells, respond in the direction of the animal's head. This makes it possible to manipulate movement information and see how the location and lead direction cells react. * The third finding was that the organization of neurons in the dorsomedial entorhinal cortex, named grid cells, closely resemble a sheet of squared paper organized in a hexagonal fashion and suggests that place cells can use grid cells to calculate distances. enter image description here Deficits of path integration, ie of these mental maps, manifest themselves at the onset of Alzheimer's disease. Decades before the expected onset of the disease subtle changes in pathway integration are also present in adults at genetic risk for Alzheimer's disease.

Previous studies of path integration have focused on tasks based on visual cues. The vestibular system is a barosensitive sensory organ, located in the inner ear, which contributes to the sensation of movement and balance in most mammals. So the study of these "path integration" maps must absolutely involve the vestibular system. This is realized in a new study published on MedRxiv, by Gillian Coughlan, Michael Hornberger and their colleagues.

One hundred and fifty participants aged 50-75 were recruited to take part in a research study at the University of East Anglia, Norwich, UK.

Saliva kits were sent to participants home and returned to the university the same day the saliva sample was taken to determine APOE genotype status. Sensor data was collected on the iPad-based assessment tool. The final sample size of 53 included 32 ε3ε3 carriers and 21 cross-sectional ε3ε4 carriers, each of whom completed the background cognitive test and vestibular task on the same day, as well as 3 homozygous APOE-ε4ε4 carriers.

The participants were asked to raise their legs (i.e. without touching the ground) and were turned over by the manipulator. Three seconds after the end of the flip, participants had to point the iPad as precisely as possible in the direction of the starting point, while still wearing the headband and earplugs. The iPad recorded vestibular data: acceleration, rotation and direction.

The scientists' results show impaired vestibular function, a deficiency in people at genetic risk for Alzheimer's disease. Vestibular function differentiated ε3ε4 carriers from ε3ε3 carriers, regardless of demographic background. Machine learning algorithms achieved significant performance in classifying genetic groups based on vestibular function, while univariate statistics failed to identify vestibular differences between APOE groups.

Animal and human studies also suggest a strong anatomical and functional interdependence between the vestibular system and the navigational system. Dysregulation of the vestibular system is associated with deficits in pathway integration.

Vestibular signals that influence pathway integration in preclinical Alzheimer's disease can help identify pathological changes before disease onset and thus guide treatment.

Identifying vestibular contributions to the cognitive phenotype of preclinical Alzheimer's disease is important because vestibular dysfunction is often present with treatable hearing loss. Additionally, vestibular balance training improved spatial orientation in monkeys with severe vestibular damage, suggesting that human adults with vestibular dysfunction, might respond to vestibular implant and/or intensive vestibular training.

Moreover, as the vestibular system has extensive connections with brain regions vulnerable to Alzheimer's disease, including the hippocampus, cingulate cortex, and parietal lobe, vestibular stimulation may indeed improve cognitive performance related to integrity of these brain regions, including disorientation and memory loss due to Alzheimer's disease.

Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease

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Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, and plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. enter image description here

In the human, adult neurogenesis has been shown to occur at low levels, and in only three regions of the brain: the lateral ventricles, the amygdala and the hippocampus.

Hippocampal neurogenesis is impaired in Alzheimer’s disease patients, yet, it is unknown whether new neurons play a causative role in memory deficits. Dans un nouvel article Rachana Mishra, Orly Lazarov and colleagues show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. An engram is the association of neuronal physical areas to external stimulus.

To examine whether the augmentation of adult hippocampal neurogenesis rescues learning and memory deficits in FAD, they generated four mouse model of familial Alzheimer disease with inducible neurogenesis. Bax gene deletion is known to enhance the survival of neural progenitor cells and led to increased neurogenesis. Bax belongs to the BCL2 family members which act as anti- or pro-apoptotic regulators, as usual, involved in a wide variety of cellular activities.

Targeted augmentation of neurogenesis in familial Alzheimer’s disease mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. enter image description here

Chemogenetic inactivation of immature neurons following enhanced neurogenesis in Alzheimer’s disease, reversed mouse performance, and diminished memory. Notably, Alzheimer’s disease-linked App, ApoE, and Adam were of the top differentially expressed genes in the engram.

Collectively, these observations suggest that defective neurogenesis contributes to memory failure in Alzheimer’s disease.

First is the direct evidence that immature neurons in the DG play a role in hippocampus-dependent memory engram in wild-type and FAD mice.

Second, impairments in hippocampal neurogenesis cause defective engram formation in FAD and underlie memory deficits.

Third, an increasing level of neurogenesis rescues memory by restoring the engram.

Fourth, immature neurons are required for proper memory formation in FAD.

Fifth, augmenting neurogenesis rescues deficits in spine density in both immature and mature engram neurons in the DG of FAD mice.

Sixth, augmenting neurogenesis modulates the profile of immature and mature engram neurons in the DG to resemble the transcription profile of engram cells in wild-type mice.

Seventh, AD-linked signals, particularly App, Apoe, and Adam, play a role in the engram and are modulated following augmentation of neurogenesis and rescue of memory.

Greater physical activity and cardiorespiratory fitness are associated with reduced age-related cognitive decline and lower risk for dementia. However, significant gaps remain in the understanding of how physical activity and fitness protect the brain from adverse effects of brain aging.

Cardiorespiratory fitness is a physiological attribute defined as the ability for circulatory and respiratory systems to deliver oxygen.

Cardiorespiratory fitness has a positive relationship with functional connectivity of several cortical networks associated with age-related decline. Furthermore it can occur independent of habitual physical activity.

A 2017 article found evidence for a shared mechanism underlying a favourable cardiovascular fitness profile and ALS susceptibility. The scientists did expose three hypothesis but this one had their favors: A genetic predisposition, for example metabolism, could lead to an increased risk of ALS and a beneficial cardiovascular risk profile. But they were unable to find evidence supporting it.

The scientists in this new publication on contrary found no association between common vascular risk factors and cognitive impairment in patients with Amyotrophic Lateral Sclerosis.

In their cohorte 870 patients, 266 had cognitive impairment. yet no cognitive burden from vascular risk factors was found in patients with Amyotrophic Lateral Sclerosis. On the contrary (and as found in many other studies), the authors first observed that type 2 diabetes mellitus and hyperlipidemia showed protective effects against cognitive decline in Amyotrophic Lateral Sclerosis.

Sensitivity analyses of gender did not substantially reverse the risk estimates. : T2DM and hyperlipidemia decrease the risk of cognitive impairment in patients with Amyotrophic Lateral Sclerosis.

So the fitness hypothesis in Amyotrophic Lateral Sclerosis seems less probable or more complex than initially stated.

Read the original article on Pubmed

Synucleinopathy in Amyotrophic Lateral Sclerosis?

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I have long thought that the subtle distinctions between neurodegenerative diseases blur the understanding instead of making things clearer.

In particular we know that ALS and FTD have something in common (TDP-43 aggregates), that Parkinson, dementia with Lewy bodies and Multiple System Atrophy are related (Alpha-synuclein aggregates (αSyn)), even some case of Alzheimer are related to ALS and FTD (Limbic-predominant age-related TDP-43 encephalopathy).

Yet an article to be published soon pushes the boundaries by hinting that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43.

Around 50 cases of ALS/Parkinson commorbidities have already been described such this one, yet suggesting there is something fundamental behind ALS and Parkinson have never been suggested.

Many neurogenerative diseases are accompanied by accumulation of protein aggregates such as extracellular amyloid-β (in Alzheimer’s disease), intraneuronal hyper-phosphorylated tau (in Alzheimer’s disease), or α-synuclein (in Parkinson’s disease).

TDP-43 pathologies are widely varied and affects different cell types and brain regions. TDP-43 was reported to co-localize with other protein species characteristic in other neurogenerative diseases, namely Huntington’s disease, Parkinson’s disease, dementia with Lewy bodies, and Alzheimer’s disease. One reason may be that TDP-43 has regions of low complexity such its C-terminal domain, which could easily bind to other proteins.

The authors found a growing body of evidence that suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. They discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.

This does not explain the colocation of those proteins. An article published a year ago might point to a little discussed suspect: Karyopherins.

Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. Most proteins require karyopherins to traverse the nuclear pore.

Karyopherins can act as importins (i.e. helping proteins get into the nucleus) or exportins (i.e. helping proteins get out of the nucleus). Energy for transport is derived from the Ran gradient.

Upon stress, several karyopherins stop shuttling between the nucleus and the cytoplasm and are sequestered in stress granules, cytoplasmic aggregates of ribonucleoprotein complexes...

Aging is by far the most prominent risk factor for Alzheimer's disease, and both aging and Alzheimer's disease are associated with apparent metabolic alterations. Perturbed cerebral glucose metabolism, an invariant pathophysiological feature of Alzheimer's disease, may be a critical contributor to the pathogenesis of this disease. For this reason, Alzheimer's disease has sometime times being called "Type 3 diabetes mellitus".

Circadian rhythms, type 2 diabetes mellitus and Alzheimer's disease are closely related and interacted with each other.
The authors of a new article on MedRxiv have previously showed circadian disruption aggravated progression of Alzheimer's disease in T2DM mice. Time-restricted feeding is shown to be a potential synchronizer. This study aims to determine whether time-restricted feeding has a protect effect against the circadian disruption-aggravated progression of Alzheimer's disease in type 2 diabetes mellitus.

Six-week-old male diabetic mice and wildtype mice were kept under normal 12:12 light/dark cycles or altered 6:18 light/dark cycles with or without time-restricted feeding period. After eight weeks, three behavioral tests (open field test, novel object recognition test, barnes maze test were performed and the circadian gene expression, body weight, lipid levels and Alzheimer's disease-associated tau phosphorylation were evaluated.
The scientists found altered light/dark cycles contributed to disruptive circadian rhythms in the hippocampus of db/db mice, while time-restricted feeding prevented this effect. time-restricted feeding also ameliorated circadian disruption-aggravated increased body weight and lipid accumulation in db/db mice.

Importantly, the db/db mice under circadian disruption showed impaired cognition accompanied by increased tau phosphorylation, whereas time-restricted feeding reversed these changes. The altered light/dark cycles only affected circadian rhythms but not other indicators like plasma/liver lipids, cognition and tau phosphorylation in the wt/wt mice.

Collectively, time-restricted feeding has a protective effect against altered light/dark cycles-aggravated Alzheimer's disease progression in diabetic mice.

Read the original article on Pubmed

Iron accumulates in the brain with age and catalyzes free radical damage to neurons, thus playing a pathogenic role in Alzheimer's disease. To decrease the incidence of Alzheimer's disease, the authors synthesized the iron-affinitive peptide 5YHEDA to scavenge the excess iron in the senile brain: YHEDAYHEDAYHEDAYHEDAYHEDA.

However, the blood-brain barrier (a layer of cells around blood vessels in central nervous system) blocks the entrance of macromolecules into the brain, thus decreasing the therapeutic effects. Several receptors present in the BBB, including transferrin, the insulin receptor, and the low-density lipoprotein receptor (LDLR), are known to allow the passage of cognate protein ligands into the brain

To facilitate the entrance of the 5YHEDA peptide, the authors linked the low-density lipoprotein receptor-binding segment of ApoB-100 to 5YHEDA. Apolipoprotein B-100 (ApoB-100) is a lipid carrier. When recognized and bound by LDLR at the BBB, the complex can be converted to an endosome, subsequently resulting in transcytosis to the abluminal side of the BBB.

There, the apolipoprotein can be released for uptake by neurons and/or astrocytes when the pH is reduced, and the receptor is recycled to the cell surface.

Lipid-interactive regions and LDLR-binding regions are scattered in ApoB-100. The primary LDLR-binding region is located between amino acids 3359 and 3367, which consists of nine amino residues with the sequence “QSDIVAHLL”. To facilitate transport of the therapeutic YHEDA peptide across the BBB, the authors added the aforementioned LDLR-binding segment in ApoB-100 to the C-terminal of the synthesized therapeutic 5-YHEDA oligomer.


Using this method, they intended to deliver 5-YHEDA into the brains of senescent (SN) mice via LDLR-mediated endocytosis.

The SN Kunming mice exhibiting AD symptoms were divided into untreated, 5-YHEDA–treated, and bs-5- YHEDA–treated groups. Two hundred microliters of 20 mM 5-YHEDA or bs-5-YHEDA solution was intracardially injected into each mouse in the latter two groups weekly. The 6-month-old mice and the aging mice that did not display SN symptoms were used as the controls. Six weeks later, all mice underwent a 4-day MWM test after 1 day of adaptation. The path that the mouse swam to return to the underwater platform and the time spent were recorded to evaluate the individual’s cognitive ability

The results of intravenous injections of bs-5YHEDA into senescent mice demonstrated that bs-YHEDA entered the brain, increased ferriportin levels, reduced iron and free radical levels, decreased the consequences of neuronal necrosis and ameliorated cognitive disfunction without kidney or liver damage. bs-5YHEDA is a safe iron and free radical remover that potentially alleviates aging and Alzheimer's disease.

The bs-5-YHEDA–treated SN mice took only 57 seconds on average and swam 220 cm to return to the hidden platform in the MWM, nearly 25 seconds faster and 90 cm less than the untreated mice and the 5-YHEDA–treated SN mice , which suggests that the synthesized bs-5-YHEDA peptide prevented the deterioration of cognition and memory in the mice.

Read the original article on Pubmed

Despite the sound epidemiologic and basic science rationales underpinning numerous "disease modification" trials in manifest Parkinson disease, none has convincingly demonstrated that a treatment slows progression.

Rapidly expanding knowledge of the genetic determinants and prodromal features of Parkinson disease now allows realistic planning of prevention trials with initiation of putatively neuroprotective therapies earlier in the disease. enter image description here In this article, the authors outline the principles of drug selection for Parkinson disease prevention trials, focused on proof-of-concept opportunities that will help establish a methodological foundation for this fledgling field.

The scientists describe prototypical, relatively low-risk drug candidates for such trials, tailored to specific at-risk populations ranging from pathogenic or gene variant carriers to those defined by prodromal Parkinson disease and α-synucleinopathy. Their proposal includes caffeine, Ibuprofen, Albuterol, Ambroxol.

Finally, the authors review gene-targeted approaches currently in development targeting clinically manifest Parkinson disease for their potential in future prevention trials.

Read the original article on Pubmed

An article published by Aileen l. Pogue of Alchem ​​Biotech Research in Canada and his colleagues at Louisiana State University discuss a pro-inflammatory toxin that may contribute to the development of Alzheimer's disease. The results are published in Frontiers in Neurology.

This article is (as usual) aggressively promoted, but probably not as new or important as its promoters would hope, nevertheless the subject is interesting even though it has made the subject of numerous scientific publications.

Intestinal dysbiosis has been implicated in the pathogenesis and progression of Alzheimer's disease by initiating and prolonging neuroinflammatory processes. Gut microbiota metabolites appear to be critical in the gut-brain axis mechanism. Gut microbiota metabolites, such as trimethylamine n-oxide, lipopolysaccharide, and short-chain fatty acids, are suggested to mediate systemic inflammation and intracerebral amyloidosis via endothelial dysfunction. New data suggest that the fungal microbiota may also influence the pathology of Alzheimer's disease.

Pogue and his colleagues believe they have found evidence that the lipopolysaccharide molecule in the human gastrointestinal (GI) tract generates an endotoxin which can perturb cells in the brain. Their paper links several recent observations linking lipopolysaccharide-induced increase in NF-kB signaling to increase in microRNA-30b.

NF-κB plays a key role in regulating the immune response to infection. Improper regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in synaptic plasticity and memory processes.

MicroRNAs (miRNAs) are short non-coding RNAs that are involved in post-transcriptional regulation of gene expression by affecting both stability and translation of mRNAs. MicroRNAs are thought to have regulatory roles through complementarity with mRNA. These microRNAs regulate a number of genes associated with breast cancer.

The authors show that an increase in miRNA-30b is able to decrease the expression of neuron-specific neurofilament light chain (NFL) messenger RNA in stressed human neuronal-glial cells cultures.

Neurofilaments provide structural support to axons and regulate axon diameter, which influences nerve conduction velocity. Neurofilament light chain depletion therefore disrupts the normal shape of neuronal cells, their cytoarchitecture and synaptic organization. Neurofilament light chains are a useful marker for monitoring disease in amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, and more recently Huntington's disease.

The presence of endotoxins, when detected in the blood, is called endotoxemia. Endotoxemia is associated with obesity, diet, cardiovascular disease and diabetes.

There is experimental and observational evidence that lipopolysaccharide may play a role in depression. Administration of lipopolysaccharide in mice can lead to depressive symptoms, and there appear to be elevated levels of lipopolysaccharide in some people with depression. Inflammation can sometimes play a role in the development of depression, and lipopolysaccharide is pro-inflammatory.

Finally, lipopolysaccharide-induced inflammation can induce cellular senescence, as has been demonstrated for lung epithelial cells and microglial cells (the latter leading to neurodegeneration).

In this study, researchers detail the pathway of BF-lipopolysaccharide from the gut to the brain and its mechanisms of action once there. For them, BF-lipopolysaccharide leaks out of the gastrointestinal tract, crosses the blood-brain barrier via the circulatory system and gains access to the cerebral compartments. Next, it increases inflammation in brain cells and inhibits neuron-specific neurofilament light (NF-L), a protein that supports cellular integrity.

A deficiency of this protein leads to progressive atrophy of neuronal cells, and ultimately to cell death, as seen in neurons affected by Alzheimer's disease. They also report that an adequate intake of dietary fiber can prevent the process.

Indeed, 60% of gut microbiome variation is attributable to diet. Therefore, modulating the gut microbiome through dietary means could be an effective approach to reduce the risk of Alzheimer's disease.

Data from animal studies have suggested that dietary fat acts as the primary macronutrient responsible for postprandial endotoxemia, and that the quantity and quality of dietary fat differentially influence metabolic endotoxemia.

Additionally, healthy diets high in unsaturated fatty acids have been associated with lower circulating levels of lipopolysaccharide, which is strongly associated with lower pro-inflammatory markers. Conversely, consumption of diets high in energy or saturated fat has been associated with increased postprandial levels of lipopolysaccharide and increased circulating levels of pro-inflammatory markers.

Since people do not eat single nutrients and instead consume a diverse range of foods and a combination of nutrients that are likely to be interacting, studying the effects of whole diets offers the possibility of accounting for the interactions between different nutrients. It is also probable that introducing variety in diet helps in having a diverse microbiome. Yet has people age, digestion becomes more difficult and aging people often prefer to not change their diet.

Thus, dietary habits may be more predictive of a real effect on the gut microbiome and Alzheimer's disease risk than foods or nutrients taken in isolation.

Can Terazosin be Repurposed to Treat ALS?

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There were 35 clinical trial of Terazosin, most recents are related to various neurodegenerative diseases. enter image description here

Terazosin, is normally used to treat symptoms of a (non cancerous) enlarged prostate and high blood pressure. It was recently discovered to increase energy levels (in the form of ATP molecules) in the brain by enhancing glycolysis.

Hypertension is prevalent in obese and diabetic patients. As soon as 1991, scientists hypothesized that people with hypertension are also likely to suffer from insulin resistance, glucose intolerance, and hyperinsulinemia.

They noted that commonly used antihypertensive agents, such as thiazide, thiazide-like diuretics, and beta-blockers, are associated with glucose intolerance and increased insulin resistance. In contrast, angiotensin-converting enzyme inhibitors, calcium antagonists, and peripheral alpha-blockers (such as prazosin and terazosin) do not adversely affect glucose tolerance or insulin sensitivity.

Yet Terazosin is not without side effects: Orthostatic hypotension, asthenia, dizziness, faintness and syncope.

Insulin stimulates glycolysis. glycolysis is an anaerobic pathway to make ATP (as opposed to the usual Krebs-cycle way, the citric acid cycle and oxidative phosphorylation).

Fixing the underlying insulin resistance would be nice, but we don't actually understand the biochemical mechanisms behind it enough to do that directly yet. Metformin is probably the closest thing, and it has several other beneficial effects as well, but we don't really understand its mechanism(s) of action either.

In 2019 Terazosin suddenly leapt into a growing pool of drugs that might have a repurposed role in Parkinson’s disease, such as exenatide, salbutamol, ursodeoxycholic acid, nilotinib, deferiprone, and ambroxol.

An article with contributors from many laboratories tell that as Terazosin stimulates glycolysis and increases cellular ATP levels, it may change the course of Parkinson’s disease. In toxin-induced and genetic Parkinson's disease models in mice, rats, flies, and induced pluripotent stem cells, Terazosin increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function.

The scientists also interrogated 2 distinct human databases and found slower disease progression, decreased Parkinson's disease-related complications, and a reduced frequency of Parkinson's disease diagnoses in individuals taking Terazosin and related drugs.

So other teams of scientists tried to replicate this success with other neurodegenerative diseases, including ALS.

In this later case, they increased activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) using Terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.

The scientists found that targeting PGK1, indeed modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour.

Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43M337V, Terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.

The team is now inviting 50 patients from the Oxford MND Care and Research Centre to participate in a feasibility study to examine the impact of terazosin on key indicators of disease progression. If this proves successful and if they find financial sponsors, they will look to move forward into a full clinical trial.

As usual, ALS mice models are not realistic, they live only 25 days when an healthy mouse lives 2 years (30 times more). As ALS in humans strikes mostly after 50 years old, a realistic mice model should live 14 months before being ill. Indeed this would create insanely long experiments, slow publication rates, and it would be costly. As in the old joke, scientists prefer to look where it's easy even if they know that current neurodegenerative diseases mice models are useless.

Let's cross our fingers, who knows, this time it may work.

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