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morganism

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Parkinsons neuron degeneration halted in mice
« on: July 02, 2020, 12:22:00 AM »
Reversing a model of Parkinson’s disease with in situ converted nigral neurons

https://www.nature.com/articles/s41586-020-2388-4

One-time treatment generates new neurons, eliminates Parkinson's disease in mice

https://www.sciencedaily.com/releases/2020/06/200625102540.htm

"Researchers have discovered that a single treatment to inhibit a gene called PTB in mice converts native astrocytes, brain support cells, into neurons that produce the neurotransmitter dopamine. As a result, the mice's Parkinson's disease symptoms disappear. "

"The treatment works like this: The researchers developed a noninfectious virus that carries an antisense oligonucleotide sequence -- an artificial piece of DNA designed to specifically bind the RNA coding for PTB, thus degrading it, preventing it from being translated into a functional protein and stimulating neuron development.

Antisense oligonucleotides, also known as designer DNA drugs, are a proven approach for neurodegenerative and neuromuscular diseases "


morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #1 on: November 21, 2020, 02:53:22 AM »
an aging article on hyperbaric effect on telomere length, and t cells

Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells : a prospective trial

https://www.aging-us.com/article/202188/text

" These intermittent hyperoxic exposures induce an adaptive response which includes increased upregulation of antioxidants genes [32] and production of antioxidants/scavengers that adjust to the increased ROS generation causing the ROS/scavenger ratio to gradually becomes similar to the ratio under a normal oxygen environment. However, because the scavenger elimination half-life (T1/2) is significantly longer than the T1/2 of ROS, upon return to normoxia, following repeated hyperoxic exposures, there are significantly higher levels of scavengers and increased antioxidant activity [13, 18]. Thus, similar to physical exercise and caloric restriction, a daily repeated HBOT protocol can induce the hormesis phenomenon. Single exposures increase ROS generation acutely, triggering the antioxidant response, and with repeated exposures, the response becomes protective [13, 18].

Additionally, intermittent hyperoxic exposures induce many of the physiological responses that occur during hypoxia [13]. HBOT induces the release of transcription factors called hypoxic induced factors (HIF) and increase their stability and activity [14]. In turn, HIF induces a cellular cascade including vascular endothelial growth factor and angiogenesis induction, mitochondria biogenesis, stem cells mobilization and SIRT1 increased activity [18]. Our study confirms increased HIF expression is induced by repetitive HBOT exposures, which gradually decreases towards normalization of HIF levels at nonmonic environment."

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #2 on: March 22, 2022, 10:40:17 PM »
Nasal spray could prevent Alzheimer’s disease, brain inflammation
March 21, 2022

The team from LSU Health New Orleans and the Karolinska Institutet in Sweden says the intranasal treatment uses pro-resolving lipid mediators to protect the brain from cognitive decline. These lipids are fatty acids, like omega-3, which are capable of easing inflammation.

This benefit is critical because neuroinflammation is a key symptom of neurodegenerative disorders like dementia. Dr. Nicolas Bazan from LSU Health discovered that neuroprotectin D1 (NPD1) is one of the lipid mediators which protects the brain.

Previous studies by Bazan’s team have found that NPD1 also protects against retinal damage and the effects of a stroke. In patients with Alzheimer’s disease, study authors say NPD1 levels in the memory area of the brain are very low.
Stopping inflammation in the brain is key

Researchers explain that undoing inflammation is no easy task. It takes mediators, cell subtypes, and communication pathways all working together to do it.

Specifically, cell communications which order the body’s protective mechanisms to turn on are necessary. This silences pro-inflammatory signaling pathways in the body. The team notes that NPD1 are one of the main signaling molecules in this process."

https://www.braintomorrow.com/2022/03/21/nasal-spray-alzheimers-memory/

https://www.nature.com/articles/s42003-022-03169-3

https://www.lsuhsc.edu/newsroom/Study%20Shows%20That%20Intranasal%20Rx%20Halts%20Memory%20Decay%20in%20Experimental%20Azheimers%20Model.html

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #3 on: April 21, 2023, 06:38:46 PM »
Study finds new pathway for clearing misfolded proteins

Stanford researchers defined a novel cellular pathway – including a “dump site” – for clearing misfolded proteins from cells. The pathway is a potential therapy target for age-related diseases like Alzheimer’s, Huntington’s, and Parkinson’s diseases

Misfolded proteins are toxic to cells. They disrupt normal functions and cause some age-related human degenerative diseases, like Alzheimer’s, Parkinson’s, and Huntington’s diseases. Cells work constantly to eliminate misfolded proteins, but these clearance mechanisms are still poorly understood.
(...)
The team identified the “garbage dump” site as the intersection of the nucleus and the vacuole – an organelle full of enzymes for degrading proteins – and showed that misfolded proteins in this “garbage dump” site are moved into the inside of the vacuole for degradation. They also showed that the pathway depends on a class of proteins used to create small vesicles for transporting molecules around cells.

“Tying that particular family of proteins and this aspect of vesicle traffic biology to protein clearance gives us a new way to look at Alzheimer’s, Parkinson’s, Huntington’s – all these neurodegenerative diseases,” said Sontag.

Cells can deal with misfolded proteins two ways: by refolding them or by eliminating them. A third option is to store them at a specific cellular location

“The communication back and forth between the nucleus and the cytoplasm was not something we expected at all,” said Sontag. “Knowing that those two compartments can kind of work together to clear garbage from everywhere was really awesome.”

“It shows that the management of misfolded proteins in the nucleus and the management of misfolded proteins in the cytoplasm are distinct but are coordinated,” said Frydman. “And what is really cool is that each compartment moves their misfolded proteins to the site where the nuclear envelope meets the vacuolar membrane.
(...)
“There’s a lot of evidence that this process for dealing with misfolded proteins slows down with age,” said Sontag. “So, as time goes on, aged cells are not able to remove all that garbage as quickly or as efficiently, and misfolded proteins build up more and more inside the cell.

https://news.stanford.edu/2023/04/20/study-finds-new-pathway-clearing-misfolded-proteins/


Nuclear and cytoplasmic spatial protein quality control is coordinated by nuclear–vacuolar junctions and perinuclear ESCRT

Effective protein quality control (PQC), essential for cellular health, relies on spatial sequestration of misfolded proteins into defined inclusions. Here we reveal the coordination of nuclear and cytoplasmic spatial PQC. Cytoplasmic misfolded proteins concentrate in a cytoplasmic juxtanuclear quality control compartment, while nuclear misfolded proteins sequester into an intranuclear quality control compartment (INQ). Particle tracking reveals that INQ and the juxtanuclear quality control compartment converge to face each other across the nuclear envelope at a site proximal to the nuclear–vacuolar junction marked by perinuclear ESCRT-II/III protein Chm7. Strikingly, convergence at nuclear–vacuolar junction contacts facilitates VPS4-dependent vacuolar clearance of misfolded cytoplasmic and nuclear proteins, the latter entailing extrusion of nuclear INQ into the vacuole. Finding that nuclear–vacuolar contact sites are cellular hubs of spatial PQC to facilitate vacuolar clearance of nuclear and cytoplasmic inclusions highlights the role of cellular architecture in proteostasis maintenance

https://www.nature.com/articles/s41556-023-01128-6?error=cookies_not_supported&code=cbd195b9-bc34-45cc-8eaa-3de99e3fa148

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #4 on: May 06, 2023, 11:49:31 PM »
Helsinki University makes Parkinson's disease breakthrough

Researchers say certain strains of gut bacteria are the likely cause of Parkinson's disease.

Scientists at the University of Helsinki on Friday said they had demonstrated that certain strains of Desulfovibrio bacteria are probable causes (siirryt toiseen palveluun) of Parkinson's disease in most cases.

This finding enables screening carriers of Desulfovibrio strains and subsequently removing the bacteria from the gut. This may make it possible to prevent Parkinson's disease.

"Our findings are significant, as the cause of Parkinson's disease has gone unknown despite attempts to identify it throughout the last two centuries. The findings indicate that specific strains of Desulfovibrio bacteria are likely to cause Parkinson's disease," professor Per Saris said in a statement.

Only a fraction of Parkinson's disease cases are caused by genetic factors, according to Saris.

"The disease is primarily caused by environmental factors, that is, environmental exposure to the Desulfovibrio bacterial strains that cause Parkinson’s disease. Only a small share, or roughly 10 percent, of Parkinson's disease is caused by individual genes," he added.

"Our findings make it possible to screen for the carriers of these harmful Desulfovibrio bacteria. Consequently, they can be targeted by measures to remove these strains from the gut, potentially alleviating and slowing the symptoms of patients with Parkinson's disease."

https://yle.fi/a/74-20030498

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Re: Parkinsons neuron degeneration halted in mice
« Reply #5 on: May 07, 2023, 03:47:17 AM »
"No compelling evidence was found to recommend the use of cannabis in PD patients. However, a potential benefit was identified with respect to alleviation of PD related tremor, anxiety, pain, improvement of sleep quality and quality of life."

 https://pubmed.ncbi.nlm.nih.gov/34958046/

https://www.bing.com/videos/search?q=parkinson%27s+disease+cured+by+cannabis&docid=603523590374379028&mid=80B940779F14B6FF1DEA80B940779F14B6FF1DEA&view=detail&FORM=VIRE
There is a principle which is a bar against all information, which cannot fail to keep a man in everlasting ignorance. That principle is contempt prior to investigation. - Herbert Spencer

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #6 on: August 05, 2023, 07:35:22 PM »
Espresso Coffee Mitigates the Aggregation and Condensation of Alzheimer′s Associated Tau Protein

Espresso coffee is among the most consumed beverages in the world. Recent studies report a protective activity of the coffee beverage against neurodegenerative disorders such as Alzheimer′s disease. Alzheimer′s disease belongs to a group of disorders, called tauopathies, which are characterized by the intraneuronal accumulation of the microtubule-associated protein tau in fibrillar aggregates. In this work, we characterized by NMR the molecular composition of the espresso coffee extract and identified its main components. We then demonstrated with in vitro and in cell experiments that the whole coffee extract, caffeine, and genistein have biological properties in preventing aggregation, condensation, and seeding activity of the repeat region of tau. We also identified a set of coffee compounds capable of binding to preformed tau fibrils. These results add insights into the neuroprotective potential of espresso coffee and suggest candidate molecular scaffolds for designing therapies targeting monomeric or fibrillized forms of tau.

https://pubs.acs.org/doi/10.1021/acs.jafc.3c01072

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #7 on: September 14, 2023, 12:48:39 AM »
Intracerebral Hemorrhage Among Blood Donors and Their Transfusion Recipients


Conclusions and Relevance 
In an exploratory analysis of patients who received red blood cell transfusions, patients who underwent transfusion with red blood cells from donors who later developed multiple spontaneous ICHs were at significantly increased risk of spontaneous ICH themselves. This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of cerebral amyloid angiopathy might explain this association.

https://jamanetwork.com/journals/jama/article-abstract/2809417

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #8 on: September 17, 2023, 09:32:57 PM »
(fascinating review on autoimmune paper from Nature here. A really simple way to short circuit the immune system attacks on internal proteins and processes. Put here because myelin is discussed.)

"Inverse vaccines" could be the beginning of the end for autoimmune disorders

(...)
Well, thanks to efforts centered at the University of Chicago, we’ve got the basics down for how to do this.  The body has ways to designate proteins as “safe” — if it didn’t, our immune system would just go crazy and attack everything — and we’ve recently learned a lot more about how that works.  In a September 7 article in Nature Biomedical Engineering, D. Scott Wilson, Jeffrey A. Hubbell, and their colleagues describe how they took advantage of this emerging knowledge to design “inverse vaccines”.

Their first successes?  Reducing pathology to zero in mice with encephalomyelitis (the mouse analog of multiple sclerosis) and reversing the established immune response to a simian immunodeficiency virus (SIV) vaccine in macaques.  What’s really important here is that an already-established immune response to something very specific can be knocked down, because that is what we will need to do to treat autoimmune disorders in humans without compromising the immune system:

    “In the past, we showed that we could use this approach to prevent autoimmunity,” said Jeffrey Hubbell, a professor of Tissue Engineering and lead author of the new research. “But what is so exciting about this work is that we have shown that we can treat diseases like multiple sclerosis after there is already ongoing inflammation, which is more useful in a real-world context.”

The great thing about the inverse-vaccine approach is that it’s actually pretty simple to implement.  People have tried nanoparticles and gene therapy and so forth to try and address the autoimmune problem, but those kinds of things are still fraught with complications.  In the study we’re talking about today, all these researchers had to do was take the protein being mistakenly attacked, put the right kind of tag on it, and inject it.  Difficulty level very similar to that of a conventional vaccine.

But how do you just stick a tag on a protein and thereby get the immune system to chill out and stop attacking it?  Well, tip your hat to the Hubbell lab, because learning that was the hard part!

It’s long been known that the liver is a bit of a safe haven from the immune system, and with good reason.  The liver is the first to encounter blood from the intestines, and it is also where old platelets and erythrocytes and other types of cells that undergo programmed cell death go to get broken down.  So the liver has to deal with a lot of stuff that is foreign and/or usually not exposed to the immune system and yet is not a threat.  That includes proteins from food, intestinal bacteria, and all those broken-down cells. 

The interesting thing is that T cells interact with the liver a lot, much more routinely than with other internal organs.  You’d think that would mean Immune Armageddon, because wouldn’t these T cells see all kinds of strange stuff in the liver and just start attacking it all?  But the liver has a special relationship with T cells.  Hepatocytes, which make up 80% of the cells in the liver, chop up proteins and show them to T cells in such a way that the T cells learn that these things are not harmful, and so the immune response to these things is blunted.  That usually works out well for the body, with the exception of a few things like hepatitis C, a virus that attacks the liver and often finagles a free pass from the immune system for this reason.

So let’s say the body is mistakenly attacking the neural protein myelin, as it does in multiple sclerosis.  Maybe we could curb that by delivering myelin protein to the hepatocytes.  They’d chew it up, show it to T cells, and convince them that it’s OK.  Then myelin-attacking T cells would change their tune, lose their anger, leave neurons alone, have a couple brews, and join us on Friday Night Beer Blog.

But how do you deliver a specific protein like myelin only to liver cells in such a way that they’ll take the myelin up, digest it, and display it the right way on their surfaces so that T cells get the message?  You can now see why people have tried nanoparticle delivery (make a little vehicle that ships myelin protein specifically to hepatocytes) or gene therapy (try to get hepatocytes to make myelin protein themselves by sticking a myelin gene into them).  But you can imagine that these things aren’t easy to do in practice.

This is where the Hubbell lab found an elegant solution.  They were able to do it because they solved a little liver puzzle in 2021.  It had been appreciated for a while that one way old dilapidated cells find their way to the liver to get broken down is by losing a certain type of sugar molecule (sialic acid) from their surfaces as part of programmed cell death.  A lot of cell-surface proteins are “glycosylated”, or coated with chains of sugar molecules, for many reasons.  Usually sialic acid is at the end of those sugar chains as a kind of protective cap.  When that sialic acid is lost, the underlying sugar molecules (often galactose, in the form of N-acetylgalactosamine) are exposed, and apparently that’s the signal for a one-way ticket to oblivion in the liver. 

Hubbell’s team showed that they could mimic this response by tagging a protein like myelin with exposed galactose molecules, to make it pose as an aging cell.  Not only would such tagged proteins find their way into the liver, but they would be processed by hepatocytes and shown to T cells.  And therefore T cells would learn not to attack them anymore.

So what this means is, let’s say you have a patient with multiple sclerosis.  You tag some myelin with a string of N-acetylgalactosamine molecules in such a way that it poses as a dilapidated cell.  This myelin is escorted to the liver and gets into hepatocytes, which then present it to T cells to convince them that myelin is “safe” and they shouldn’t attack it anymore.

This worked so well in mice I literally recoiled from the graph below when I first saw it.  Mice were first intentionally made to have simulated multiple sclerosis, so that they were prone to myelin attack by their own immune systems.  This was done by injecting them with T cells generated in other mice that had been vaccinated with a big chunk of the myelin protein (called MOG) and also with Complete Freund’s Adjuvant (CFA), which is basically dried bacteria to spook the immune system into action.  So these donated T cells were ready to hit the ground running and attack myelin in the recipient mice.

This transfer of activated T cells from mouse to mouse is called “adoptive transfer”, so when you see it in the figure below, you’ll know what that is.  That happened at “Day 0”.  Then the recipient mice were also treated with inverse vaccine (“pGal-MOG”) on Days 0, 3, and 6 to see if the multiple sclerosis effect could be countered.

This graph — yes, the one I recoiled from — shows what happens if you treat such mice with saline solution as a control (they get the disease), if you treat them with plain old untagged MOG (they get the disease), if you treat them with an antibody called α-VLA-4 that should delay onset of disease by blocking T cells from accessing the brain (they get the disease after a few days’ delay), and finally if you treat them with inverse vaccine, or galactose-tagged MOG (green circles).  In the last case, the green circles form a flat line at zero.  The disease is absolutely stopped cold.

They saw the same thing in a different mouse multiple sclerosis model where the disease comes on, then relapses, then comes on again.  Relapse happened in all the controls, but when the mice were treated with pGal-MOG (the galactose-tagged myelin), there was no relapse.  This is especially important because it means that the treatment can subdue an immune response that is already underway, such as in humans with autoimmune disorders.

Before we go pumping this inverse vaccine into human beings, it would be nice to see some effectiveness in other primates.  Autoimmune “disease model” primates are not really widely available, so we need to test this out in a different way.  We can do that by vaccinating primates against something so that they develop a strong immune response to it, then seeing if we can quell that immune response with our inverse vaccine.

That was done with macaques and simian immunodeficiency virus (SIV) here.  Two sets of macaques were injected with an SIV vaccine three times (at weeks 0, 6, and 12), and they all generated a vigorous immune response.  Then at weeks 18, 22, and 26, they got either the inverse vaccine or saline solution as a control.

In this case the inverse vaccine is a tagged version of one of the proteins made by SIV called Nef.  So we want to see if the inverse vaccine can tamp down the strong T-cell response to Nef in these macaques.  In other words, can the inverse vaccine put the brakes on a strong immune response that is already underway, as happens in an autoimmune disease, in a primate?

Right after the first inverse-vaccine treatment at 18 weeks, the T-cell response to Nef is indeed cut dramatically (-40% for inverse vaccine vs. +100% for the control), and then it gradually diminishes in both sets of macaques, as expected.

All of this together means that we now have an elegant way to designate specific proteins as “safe”, and thus convince the immune system to stop attacking them.  Keep in mind that this is only version 1.0 with short treatments.  We’ll absolutely get better at this over time.

Phase I clinical trials are underway, and so far celiac patients (for whom the immune system flips out over gluten) have had the inverse vaccine administered safely.  That’s what you like to see in Phase I.  No complications developing.  Next up is Phase II, where we begin to look at efficacy in humans. 

If you’ve been following immune-system research over the last few years, you probably agree with me that we are in a golden age of understanding, where we are starting to have a real shot at subduing diseases that have plagued us since before we even started walking upright.  Multiple sclerosis, Crohn’s disease, rheumatoid arthritis, lupus, celiac disease, Type I diabetes, myasthenia gravis, ulcerative colitis, psoriasis, ….  the list goes on.  We’re on an irreversible path to defeating each and every one of these.  All of their days are numbered.  It is only a matter of time.

https://www.dailykos.com/stories/2023/9/15/2193137/--Inverse-vaccines-could-be-the-beginning-of-the-end-for-autoimmune-disorders


Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses

Abstract

Inducing antigen-specific tolerance during an established immune response typically requires non-specific immunosuppressive signalling molecules. Hence, standard treatments for autoimmunity trigger global immunosuppression. Here we show that established antigen-specific responses in effector T cells and memory T cells can be suppressed by a polymer glycosylated with N-acetylgalactosamine (pGal) and conjugated to the antigen via a self-immolative linker that allows for the dissociation of the antigen on endocytosis and its presentation in the immunoregulatory environment. We show that pGal–antigen therapy induces antigen-specific tolerance in a mouse model of experimental autoimmune encephalomyelitis (with programmed cell-death-1 and the co-inhibitory ligand CD276 driving the tolerogenic responses), as well as the suppression of antigen-specific responses to vaccination against a DNA-based simian immunodeficiency virus in non-human primates. Our findings show that pGal–antigen therapy invokes mechanisms of immune tolerance to resolve antigen-specific inflammatory T-cell responses and suggest that the therapy may be applicable across autoimmune diseases.

https://www.nature.com/articles/s41551-023-01086-2?error=cookies_not_supported&code=72708bb2-d432-4170-8fff-9d9b7b634452



(and the previous paper discussed in article)

Soluble N-Acetylgalactosamine-Modified Antigens Enhance Hepatocyte-Dependent Antigen Cross-Presentation and Result in Antigen-Specific CD8+ T Cell Tolerance Development

https://www.frontiersin.org/articles/10.3389/fimmu.2021.555095/full#B44

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #9 on: December 10, 2023, 11:18:58 PM »
(This is another attack on the myelin sheaths.  remember...to donate blood, it gets rid of excess iron.)

A new study, led by scientists at Oregon Health & Science University and published online in the journal Annals of Neurology on Aug. 21, reveals for the first time that a form of cell death known as ferroptosis — caused by a buildup of iron in cells — destroys microglia cells, a type of cell involved in the brain’s immune response,  in cases of Alzheimer’s and vascular dementia.

The researchers conducted the study examining post-mortem human brain tissue of patients with dementia.

“This is a major finding,” said senior author Stephen Back, M.D., Ph.D., a neuroscientist and professor of pediatrics in the OHSU School of Medicine.

Back has long studied myelin, the insulation-like protective sheath covering nerve fibers in the brain, including delays in forming myelin in premature infants. The new research extends that line of work by uncovering a cascading form of neurodegeneration triggered by deterioration of myelin. They made the discovery using a novel technique developed by the study’s lead author Philip Adeniyi, Ph.D., a postdoctoral researcher in Back’s laboratory.

The researchers discovered that microglia degenerates in the white matter of the brain of patients with Alzheimer’s and vascular dementia.

Microglia are resident cells in the brain normally involved in clearing cellular debris as part of the body’s immune system. When myelin is damaged, microglia swarm in to clear the debris. In the new study, researchers found that microglia themselves are destroyed by the act of clearing iron-rich myelin — a form of cell death known as ferroptosis.

Given the intense scientific focus on the underlying cause of dementia in older adults, Back called it amazing that researchers hadn’t made the connection to ferroptosis until now.

“We’ve missed a major form of cell death in Alzheimer’s disease and vascular dementia,” Back said. “We hadn’t been giving much attention to microglia as vulnerable cells, and white matter injury in the brain has received relatively little attention.”
(more)

https://news.ohsu.edu/2023/09/05/ohsu-scientists-discover-new-cause-of-alzheimers-vascular-dementia


Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration

https://www.nature.com/articles/s41593-022-01221-3?error=cookies_not_supported&code=bf06e6a5-5c24-405d-93cb-a8884f5dfa78

Microglial Activation in Metal Neurotoxicity: Impact in Neurodegenerative Diseases

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9904912/


The role of iron in brain ageing and neurodegenerative disorders

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672917/

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Re: Parkinsons neuron degeneration halted in mice
« Reply #10 on: December 13, 2023, 11:26:38 PM »
Quote
(This is another attack on the myelin sheaths.  remember...to donate blood, it gets rid of excess iron.)

Donating blood is good for other reasons so if you do it for that reason that is good too but your claim sounds too much like bloodletting.

The build up at cellular level is driven by very different processes and you can´t bleed your way out of that.
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morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #11 on: December 14, 2023, 08:19:58 AM »
yeah, i'm Not a leach guy.... but if it works for the Stones....

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Re: Parkinsons neuron degeneration halted in mice
« Reply #12 on: December 14, 2023, 03:51:48 PM »
Without having much insight in these topics, I would appreciate a straight, understandable answer to a rather simple question, which came to my mind, as I browsed through this thread:

Could there be a connection between excessive intake of red wine, accumulation of oxidised iron compounds in the brain and dementia?

kassy

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Re: Parkinsons neuron degeneration halted in mice
« Reply #13 on: December 14, 2023, 05:50:22 PM »
Quote
He said the underlying cause initiating the cycle of decline likely relates to repeated episodes of low blood flow and oxygen delivery to the brain over time due to acute stroke or chronic conditions such as hypertension and diabetes.

From the recent article.

Quote
Iron is the most abundant transition metal in the brain1. Disrupted iron homeostasis2 is correlated with disease progression in several neurodegenerative disorders, including Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)3,4. Microglia have one of the highest iron storage capacities of all brain cell types and accumulate iron in disease1,5,6,7,8,9, but how iron overload impacts microglia function and whether iron-laden microglia contribute to neurodegeneration is not well understood.

From the paper.

There are many different causes. The causes listed in the first quote are related to more direct damage as are lots of headers in soccer or playing rugby.

No idea if you can achieve that with too much wine but i doubt it. There will probably be liver problems way before that. 
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SteveMDFP

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Re: Parkinsons neuron degeneration halted in mice
« Reply #14 on: December 14, 2023, 06:03:58 PM »
Without having much insight in these topics, I would appreciate a straight, understandable answer to a rather simple question, which came to my mind, as I browsed through this thread:

Could there be a connection between excessive intake of red wine, accumulation of oxidised iron compounds in the brain and dementia?

Moderate wine consumption might (or might not) be helpful:

Relationship of Wine Consumption with Alzheimer’s Disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019227/

One confounding variable is that quite a few people with almost any chronic disease may avoid any alcohol.  They then, as a group, tend to have worse health outcomes, of almost any kind examined.  This can potentially lead to conclusions that alcohol can be protective (in moderate amounts)  Heavy drinkers tend to have worse outcomes, certainly including dementia.

Any controlled, randomized clinical trial of alcohol use would likely be deemed unethical, so we'll likely never know with any certainty.  But epidemiological evidence suggests that moderate use is fine, generally.

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #15 on: December 15, 2023, 07:11:17 AM »
( I don't think any food has such a direct influence on the brain. The problems may come from viruses that move along the myelin sheaths of nerves, ruptured sinus cavities, and blood borne pathogens that can get thru. The biggest culprit i have seen was the paper that claimed that maltose sugar, a regular food additive could cause the BBBarrier to open for about 20 min after ingestion.
 {old style ice cream, beer, shakes}
That could allow anything that didn't go thru the liver or kidneys to potentially get to the brain.
Too bad they don't use that in the treatment for brain cancers.)


Basic physiology of the blood-brain barrier in health and disease: a brief overview

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849738/


Signatures for viral infection and inflammation in the proximal olfactory system in familial Alzheimer's disease
Neurobiology of Aging Volume 123, March 2023


(this one from 2022, and the same crew may have published one on smoking reducing brain volume last week)

Associations between alcohol consumption and gray and white matter volumes in the UK Biobank

Nature Communications volume 13, Article number: 1175 (2022)



vox_mundi

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Re: Parkinsons neuron degeneration halted in mice
« Reply #16 on: December 19, 2023, 04:23:33 PM »
Massive Drug Search Uncovers Infinitesimal Molecule That Kills Cancers While Sparing Immune Cells
https://medicalxpress.com/news/2023-12-massive-drug-uncovers-infinitesimal-molecule.html

Scientists have found an experimental small molecule that induces a form of cell death to kill a variety of cancers while enhancing the power of the immune system and leaving healthy cells totally unscathed.

The molecule triggers ferroptosis, a unique form of cell death that is increasingly being tested as an anti-cancer strategy. The international team of scientists have reported their findings in the journal Science Translational Medicine.

... Even though ferroptosis is being actively pursued as a potential cancer treatment, other researchers are studying the process for its pathological role in a variety of disparate diseases that range from Alzheimer's, cardiovascular disease to even various forms of cancer. Ferroptosis is intimately involved in the disease processes of these conditions, studies have shown.

In terms of harnessing this form of cell death as a therapeutic, teams worldwide are racing to overcome a number of conundrums, especially what's known as the "non-selective" activities of ferroptotic cell death. It doesn't just kill cancer cells, it kills a multitude of cells in the immediate micro-environment, particularly the Big Three: dendritic cells, T cells and neutrophils, which seemingly defeats the promise that ferroptosis holds as a cancer fighter.

That means most compounds capable of inducing ferroptosis in cancer cells may also inflict the same fate on various immune cells, weakening the immune system's ability to swoop in and wage war on deadly tumors.

Now, Li and a far-flung team of collaborators on three continents have pinpointed a promising small molecule called N6F11, which not only triggers ferroptotic cell death, it also selectively causes the degradation of glutathione peroxidase-4, also known as GPX4, a notorious blocker of ferroptosis.

Li and colleagues, who went on a wide-ranging drug hunt, screening a slew of compounds to find N6F11 and its unique properties, say with N6F11 in the mix, ferroptosis can be triggered and GPX4 is no longer in the way to prevent this specialized form of cell death from annihilating tumors. Even more eye-opening, N6F11 degraded GPX4 in human pancreatic, bladder, breast, and cervical cancer cells without affecting GPX4 in that vital trio of the immune system: dendritic cells, T cells and neutrophils.

Li, along with colleagues from Columbia University in New York, Université de Paris in France, a large team at UT Southwestern Medical Center in Dallas and beyond, also found that N6F11 slowed the growth of active tumors in mouse models inoculated with pancreatic cancer cells. The animals endured the treatment without severe side effects—an effect the authors tied to N6F11's ability to stimulate T cells.

Jingbo Li et al, Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer, Science Translational Medicine (2023)
https://www.science.org/doi/10.1126/scitranslmed.adg3049

... Inducing ferroptotic cell death is an emerging treatment for cancer; however, because of its non-selective properties, it can also inhibit the immune cells. To overcome this, Li et al. have identified a small molecule compound, N6F11, that selectively triggered degradation of glutathione peroxidase 4 (GPX4), a ferroptosis repressor, in tumor cells and not immune cells. The authors further tested this in mouse models of pancreatic cancer, demonstrating that treatment increased sensitivity to immune checkpoint blockade (ICB). These preclinical results warrant further study of N6F11 and its potential benefit to improve efficacy of ICB in patients with cancer.
There are 3 classes of people: those who see. Those who see when they are shown. Those who do not see

Insensible before the wave so soon released by callous fate. Affected most, they understand the least, and understanding, when it comes, invariably arrives too late

Fiat iustitia, et pereat mundus

kassy

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Re: Parkinsons neuron degeneration halted in mice
« Reply #17 on: December 19, 2023, 06:22:19 PM »
Identical Twins Mystery: When 1 Has Dementia, Both Face a Shorter Life

When someone is diagnosed with dementia, a common question their families may ask is: 'How much time do we have?' How much time before their loved one drifts away; after their memories fade and confusion sets in?


Answering that difficult question can be tricky, as life expectancy after a dementia diagnosis varies from around 3 to 7 years and can be more or less depending on the person's age and the type of dementia they've developed.

Generally, though, people with dementia tend to have shorter lifespans than otherwise healthy folks. And so might their seemingly unaffected twins, a new study suggests.

This strange connection is the result of a large study of hundreds of Swedish twins, where one twin was diagnosed with dementia and the other was not.

The study also included a larger analysis of almost 1,000 people with dementia, who happened to be a twin, and nearly 3,000 healthy people, also twins, though not necessarily siblings of the affected individuals.

Unsurprisingly, people without dementia outlived those with the condition. Moreover, the researchers found those with dementia lived on average 7 years after diagnosis, confirming previous estimates.

Unexpectedly, identical twin pairs had similar life expectancies after one sibling was diagnosed with dementia.

The findings suggest the increased risk of a shorter lifespan associated with dementia might extend to a person's cognitively-unaffected twin, raising questions about how much genetics – as opposed to the disease itself or environmental factors – are at play in their early death.

Jung Yun Jang, a medical researcher at the University of California Irvine and lead author of the study, explains: "We assumed the reason a person who has developed dementia has a shortened life expectancy is because the dementia leads to other medical conditions that affect mortality," she says.

"What we're seeing instead is the increased risk of mortality is not due to just the dementia itself, but also a whole package of other influences that the person brings to their disease."

https://www.sciencealert.com/identical-twins-mystery-when-1-has-dementia-both-face-a-shorter-life

Þetta minnismerki er til vitnis um að við vitum hvað er að gerast og hvað þarf að gera. Aðeins þú veist hvort við gerðum eitthvað.

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #18 on: December 30, 2023, 08:35:02 PM »
(candida albacans opens blood/brain barrier, and produces amyloid beta agglomerates)

Brain fungal infection produces Alzheimer's disease-like changes

“Our first question was, how does C. albicans enter the brain? We found that C. albicans produces enzymes called secreted aspartic proteases (Saps) that breakdown the blood-brain barrier, giving the fungus access to the brain where it causes damage,

(snip)
Corry and his colleagues had previously shown that a C. albicans brain infection is fully resolved in otherwise healthy mice after 10 days. In this study, they reported that this occurred thanks to two mechanisms triggered by the fungus in brain cells called microglia.
 
“The same Saps that the fungus uses to break the blood-brain barrier also break down the amyloid precursor protein into Ab-like peptides,” Wu said. “These peptides activate microglial brain cells via a cell surface receptor called Toll-like receptor 4, which keeps the fungi load low in the brain, but does not clear the infection.”
C. albicans also produces a protein called candidalysin that also binds to microglia via a different receptor, CD11b. “Candidalysin-mediated activation of microglia is essential for clearance of Candida in the brain,” Wu said. “If we take away this pathway, fungi are no longer effectively cleared in the brain.”
 
“This work potentially contributes an important new piece of the puzzle regarding the development of Alzheimer’s disease,” Corry said. “The current explanation for this condition is that it is mostly the result of the accumulation of toxic Ab-like peptides in the brain that leads to neurodegeneration. The dominant thinking is that these peptides are produced endogenously, our own brain proteases break down the amyloid precursor proteins generating the toxic Ab peptides.”
 
Here, the researchers show that the Ab-like peptides also can be generated from a different source – C. albicans. This common fungus, which has been detected in the brains of people with Alzheimer’s disease and other chronic neurodegenerative disorders, has its own set of proteases that can generate the same Ab-like peptides the brain can generate endogenously.
 
“We propose that the brain Ab-peptide aggregates that characterize multiple Candida-associated neurodegenerative conditions including Alzheimer’s disease, Parkinson’s disease and others, may be generated both intrinsically by the brain and by C. albicans,” Corry said. “These findings in animal models support conducting further studies to evaluate the role of C. albicans in the development of Alzheimer’s disease in people, which can potentially lead to innovative therapeutic strategies.”

https://www.bcm.edu/news/brain-fungal-infection-produces-alzheimers-disease-like-changes

https://studyfinds.org/fungus-alzheimers-disease/

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #19 on: February 20, 2024, 11:42:46 PM »
 Blocking key protein may halt progression of Alzheimer’s disease

AURORA, Colo. (Feb. 20, 2024) – Researchers at the University of Colorado Anschutz Medical Campus have found that inhibiting a key protein can stop the destruction of synapses and dendritic spines commonly seen in Alzheimer’s disease.

The study, whose first author is Tyler Martinez, a student in the Pharmacology and Molecular Medicine PhD program at the University of Colorado School of Medicine, was published recently in the journal eNeuro.

The researchers, using rodent neurons, found that targeting a protein called Mdm2 with an experimental cancer drug known as nutlin, stopped neurotoxic amyloid-b peptides that accumulate in Alzheimer’s disease (AD) from overly pruning synapses.

“Cognitive impairments associated with AD correlate with dendritic spine and excitatory synapse loss, particularly within the hippocampus,” said the study’s senior author Professor Mark Dell’Acqua, PhD, vice-chair of the Department of Pharmacology at the CU School of Medicine.

Dell’Acqua said trimming excess dendritic spine synapses is normal in the post-natal brain but can be abnormally accelerated in AD causing loss of memory and learning.

“When this protein Mdm2 is turned on inappropriately it leads to pruning of the synapses when amyloid-b is present,” he said. Amyloid-b is the main component of amyloid plaques found in the brain of those with AD. “When we used the drug that inhibits Mdm2 on the neurons it completely blocked dendritic spine loss triggered by amyloid-b. So inhibiting this protein is clearly working.”

Dendritic spines protrude from dendrites, a component of neurons, and receive synaptic signals that are critical in learning and memory.

Dell’Acqua, director of the Neurotechnology Center at the CU School of Medicine, noted that much of the research into AD therapies tends to focus on eradicating amyloid plaques in the brain.

“There are questions if anti-amyloid therapy is the be all and end all of AD therapy,” he said. “Even if you could tolerate the high cost, the effectiveness is questionable. We are saying that it may also be possible to intervene in the process by blocking some of the impacts of amyloid-b. And you could intervene by targeting Mdm2.”

The next step is determining whether they can block AD progression in an animal model. If so, human trials could happen in the future. Drugs that target Mdm2 are already developed and in clinical trials for cancer but still need FDA approval.

https://www.eurekalert.org/news-releases/1034981


Amyloid-β-induced dendritic spine elimination requires Ca2+-permeable AMPA receptors, AKAP-Calcineurin-NFAT signaling, and the NFAT target gene Mdm2

https://www.eneuro.org/content/early/2024/02/07/ENEURO.0175-23.2024

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #20 on: February 26, 2024, 12:24:50 AM »
Is the 100-year old TB vaccine a new weapon against Alzheimer’s? 

Studies suggest the BCG jab discovered a century ago could provide a cheap and effective way of boosting the immune system to protect people from developing the condition

(...)
he idea may sound far-fetched, but decades of research show that BCG can have surprising and wide-ranging benefits that go way beyond its original purpose. Besides protecting people from TB, it seems to reduce the risk of many other infections, for instance. In a recent clinical trial, BCG halved the odds of developing a respiratory infection over the following 12 months, compared with the people receiving a placebo.

BCG is also used as a standard treatment for forms of bladder cancer. Once the attenuated bacteria have been delivered to the organ, they trigger the immune system to remove the tumours, where previously they had passed below the radar. “It can result in remarkable disease-free recoveries,” says Prof Richard Lathe, a molecular biologist at Edinburgh University.

These remarkable effects are thought to emerge from a process called “trained immunity”. After an individual has received BCG, you can see changes in the expression of genes associated with the production of cytokines – small molecules that can kick our other defences, including white blood cells, into action. As a result, the body can respond more efficiently to a threat – be it a virus or bacteria entering the body, or a mutant cell that threatens to grow uncontrollably. “It can be likened to upgrading the security system of a building to be more responsive and efficient, not just against known threats but against any potential intruders,” says Weinberg.

There are good reasons to believe that trained immunity could reduce the risk of Alzheimer’s. By bolstering the body’s defences, it could help keep pathogens at bay before they reach the brain. It could also prompt the brain’s own immune cells to clear away the amyloid beta proteins more effectively, without causing friendly fire to healthy neural tissue.

Animal studies provide some tentative evidence. Laboratory mice immunised with BCG have reduced brain inflammation, for example. This results in notably better cognition, when other mice of the same age begin to show a steady decline in their memory and learning. But would the same be true of humans?

To find out, Ofer Gofrit of the Hadassah-Hebrew University Medical Centre in Jerusalem and his colleagues collected the data of 1,371 people who had or had not received BCG as part of their treatment for bladder cancer. They found that just 2.4% of the patients treated with BCG developed Alzheimer’s over the following eight years, compared with 8.9% of those not given the vaccine.

Since the results were published in 2019, other researchers have replicated the findings. Weinstein’s team, for instance, examined the records of about 6,500 bladder cancer patients in Massachusetts. Crucially, they ensured that the sample of those who had received BCG and those who hadn’t were carefully matched for age, gender, ethnicity and medical history. The people who had received the injection, it transpired, were considerably less likely to develop dementia.

The precise level of protection varies between studies, with a recent meta-analysis showing an average risk reduction of 45%. If this can be proven with further studies, the implications would be huge. “Simply delaying the development of Alzheimer’s by a couple of years would lead to tremendous savings – both in suffering and our money,” says Prof Charles Greenblatt of the Hebrew University of Jerusalem, who was a co-author of Gofrit’s original paper.

Plenty of caution is necessary. The existing papers have all examined patients with bladder cancer, but as yet there is little data on the general population. One obvious strategy may be to compare people who have received the BCG vaccine during childhood with those who hadn’t, but the effects of BCG may dwindle over the decades – long before most people would be in danger of developing Alzheimer’s.
A person being injected in the arm with a syringe.
While BCG is thought to provide the most potent immune training, other vaccines such as the flu jab may also stimulate the body’s defences. Photograph: David Cheskin/PA

We can, however, examine the effects of other vaccines delivered in old age. With its live (but attenuated) bacteria, BCG is thought to provide the most potent immune training, but other vaccines may also stimulate the body’s defences. Consider the flu jab. Nicola Veronese of the University of Palermo in Italy and her colleagues recently analysed the results of nine studies, many of which controlled for lifestyle factors, including income, education, smoking, alcohol consumption and hypertension. The team found that the influenza vaccine was associated with a 29% reduced risk of dementia. “Two studies also showed an association between the number of doses, over previous years, and the incidence of dementia,
(more)

https://www.theguardian.com/society/2024/feb/25/is-the-100-year-old-tb-vaccine-a-new-secret-weapon-against-alzheimers-dementia-bcg

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #21 on: April 26, 2024, 09:13:55 AM »
(another article warning on myelin sheath destruction)



(...)
“We’re not looking to say that there’s a direct correlation between exposure and human neurodevelopmental issues. We don’t have that data yet,” said Paul Tesar, the director of the Institute for Glial Sciences at Case Western Reserve and the principal investigator of the study. “But we have fundamentally shown, very rigorously, that oligodendrocytes have a specific vulnerability to these chemicals.”

There are hundreds of quaternary ammonium compounds, which can make it hard to identify the chemicals on an ingredient list. Quats often end with “ammonium chloride” or “onium chloride” in the name. One common quaternary ammonium compound in hand soaps, for instance, is benzalkonium chloride. Google can also help you figure out whether a particular ingredient in a cleaning product is a quaternary ammonium compound.

The American Cleaning Institute, a trade association for cleaning product makers, downplayed the findings. Brian Sansoni, senior vice president of communications, wrote in an email that the study “does not establish a causal link to any known or observed human health effect and should not be interpreted by readers to be predictive of possible health effects.”
Advertisement

“Surface disinfecting products, including those with quaternary ammonium compounds, are highly regulated and extensively evaluated for safety according to their approved uses,” Sansoni wrote. “Quats are a critical public health solution across homes, schools, health care settings and communities every single day. ”
What to know about brain health and quats

The research on quaternary ammonium compounds doesn’t mean we should stop disinfecting our homes, experts say. But it’s good to be aware of the chemicals in your household cleaners, and to make informed decisions about which products you choose.

Erin Cohn, a graduate student in Tesar’s lab and the lead author of the study, said oligodendrocyte dysfunction is linked to various neurological conditions. In cases of multiple sclerosis, for instance, the body’s immune system attacks the insulation created by oligodendrocytes.
Advertisement

To study quats, the researchers used stem cells to grow human brain organoids — petri dishes of tiny, “millimeter-sized brain tissue” — intended to mimic early stages of brain development, Tesar said. And they found the quaternary ammonium compounds specifically killed oligodendrocytes but not the other cell types.

The researchers also fed the chemicals to young mice for 10 days. In autopsies, they found exposure to quats had “caused a selective loss of oligodendrocytes” in the brain, Tesar said.

“The science is clear that these chemicals have harmful effects on oligodendrocytes,” Tesar said. What’s not clear is whether “everyday exposure” to these chemicals affects the human brain.
(more)

https://www.washingtonpost.com/wellness/2024/04/25/disinfectants-quaternary-ammonium-compounds/

SteveMDFP

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Re: Parkinsons neuron degeneration halted in mice
« Reply #22 on: April 26, 2024, 05:00:48 PM »
Since content in this thread now includes Alzheimer's, and species other than mice are relevant, perhaps the name of the thread should be changed to "Research on halting neuron degeneration"?

Sigmetnow

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Re: Parkinsons neuron degeneration halted in mice
« Reply #23 on: May 04, 2024, 06:03:33 PM »
Brain Autopsies Reveal Potential New Culprit Behind Alzheimer's Disease
Quote
Analysis of human brain tissue reveals differences in how immune cells behave in the brains with Alzheimer's disease compared to healthy brains, indicating a potential new treatment target.

The University of Washington-led research discovered microglia in the brains of people with Alzheimer's disease were in a pre-inflammatory state more frequently, making them less likely to be protective.

Microglia are immune cells that help keep our brains healthy by clearing waste and preserving normal brain function. In response to infection or to clear out dead cells, these nifty shape-shifters can become less spindly and more mobile to engulf invaders and rubbish. They also 'prune' synapses during development, which helps shape the circuitry for our brains to function well.

It's less certain what part they play in Alzheimer's, but in people with the devastating neurodegenerative disease, some microglia respond too strongly and may cause inflammation that contributes to the death of brain cells. Unfortunately, clinical trials of anti-inflammatory medications for Alzheimer's haven't shown significant effects.

Using a new method to enhance single-nucleus RNA sequencing, the team was able to identify in depth 10 different clusters of microglia in the brain tissue based on their unique set of gene expression, which tells the cells what to do.

The microglia types in the brains of people with Alzheimer's disease were less likely to be protective, compromising their ability to pull their weight in cleaning up dead cells and waste and promoting healthy brain aging.

 
The scientists also think microglia can change types over time. So we can't just look at a person's brain and say for sure what type of microglia they have; keeping track of how microglia change over time could help us understand how they contribute to Alzheimer's disease.

"At this point, we can't say whether the microglia are causing the pathology or whether the pathology is causing these microglia to alter their behavior," says Prater.

"Now that we have determined the genetic profiles of these microglia, we can try to find out exactly what they are doing and hopefully identify ways to change their behaviors that may be contributing to Alzheimer's disease," Prater says.

"If we can determine what they are doing, we might be able to change their behavior with treatments that might prevent or slow this disease."

The study has been published in Nature Aging.
https://www.sciencealert.com/brain-autopsies-reveal-potential-new-culprit-behind-alzheimers-disease
People who say it cannot be done should not interrupt those who are doing it.

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #24 on: May 06, 2024, 08:56:18 PM »
Modified sugar molecules boost stem cell therapy for brain repair after cardiac arrest

Brain injury is the most common consequence of cardiac arrest, due to the impaired blood flow and oxygen to the brain. About 70 percent of the nearly 7 million people who suffer from cardiac arrest each year experience a long-term brain injury that leads to permanent disability.

The potential of stem cell therapy to address neurological dysfunction has long been fraught with challenges due to the harsh in vivo microenvironment of the brain; this results in poor stem cell retention and integration at the site of injuries.

Recent advances in manipulating a cell’s complex carbohydrate structure through metabolic glycoengineering, has enabled UMSOM researchers to explore the efficacy of a modified sugar molecule, known as the TProp sugar analog, to help stem cells remain more viable in the brain.
(snip)
In the study, researchers examined the efficacy in a rat model and compared the effects of “naïve” human neural stem cells to neural stem cells that were pretreated with the “TProp” sugar analog. The study found that stem cells pretreated with TProp, substantially improved brain function and reduced anxiety and depression-associated behaviors through various behavioral tests.

The treatment also activated the related inflammatory Wnt/β-catenin signaling pathway, which regulates critical aspects of cell function. This upregulated pathway by TProp promotes the transition of stem cells into neurons, the nerve cells responsible for sending and receiving signals from the brain.

The TProp-pretreated group also demonstrated improved synaptic plasticity, the ability of neurons to modify the strength of their connections, and reduced neuroinflammation in the central nervous system, providing a superior ability to regenerate and recover from damaged brain functions.

The results indicate that glycoengineered stem cells have the potential to promote the growth of new connections among surviving or regenerated neurons, leading to regenerated circuits in the brain.

“This innovative research has been an important proof of concept study suggesting that stem cells could be used to regenerate neural connections in the brain of patients who suffer a devasting injury after cardiac arrest”, said Dean Mark T. Gladwin, MD, who is the John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM, and Vice President for Medical Affairs, University of Maryland, Baltimore. “Next steps for this translational application include determining the optimal delivery route and timing of metabolically glycoengineered stem cell therapy, as well as systemic evaluation on large animals before this can move into clinical studies.”

https://www.news-medical.net/news/20240506/Modified-sugar-molecules-boost-stem-cell-therapy-for-brain-repair-after-cardiac-arrest.aspx


The pivotal study was funded by the National Institute of Neurological Disorders and Stroke (R01NS125232, R01NS110387), and featured on the April Vol. 34 No.17 front cover of Advanced Functional Materials Journal.

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #25 on: May 08, 2024, 08:36:30 PM »
Effectiveness of Personalized Hippocampal Network–Targeted Stimulation in Alzheimer Disease
A Randomized Clinical Trial  (trans-cranial magnetic stim coils)

(...)

Introduction

Alzheimer disease (AD) is a neurodegenerative disorder characterized by amyloid accumulation in the brain. While only symptomatic treatments have been available, recent approval of antiamyloid monoclonal antibodies has offered potential disease-modifying therapies.1 However, given diverse and complex pathological mechanisms, additional therapeutic interventions are still essential for advancing AD management. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe potential intervention for AD, with recent clinical trials suggesting improved cognition.2-5

The choice of stimulation site is crucial for rTMS efficacy.6 Although the dorsolateral prefrontal cortex (DLPFC) or precuneus have been common target sites,3,7-11 the optimal target for rTMS should align with individual disease characteristics and available treatment mechanisms. Early-stage AD has hippocampal atrophy,12 leading to functional disconnection with other brain regions, particularly the parietal cortex.13,14 Network-targeted rTMS has shown promising results in enhancing interregional functional magnetic resonance image (fMRI) activity within the posterior-medial hippocampal-cortical network.15-19 Consequently, rTMS targeting parietal sites could enhance memory performance without directly stimulating the deeply located hippocampus.15,20 In addition to selecting stimulation sites, accurate targeting also matters. Personalized stimulation using neuro-navigation systems has been explored to ensure accurate TMS coil positioning.20 However, its application in clinical settings can be challenging due to time and resource constraints.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2818365

Key Points

Question  Can 4-week personalized hippocampal network–targeted stimulation improve cognition in Alzheimer disease?

Findings  In this randomized clinical trial including 30 participants, personalized hippocampal network–targeted stimulation demonstrated a significant improvement in cognition and functional performances compared with the sham group at 8 weeks, with significant improvements evident at 4 weeks after the end of stimulation. Stimulation also increased functional connectivity between the hippocampus and precuneus, with changes correlated with improvements in cognition.

Meaning  These results suggest that personalized hippocampal network–targeted stimulation could be considered as a viable nonpharmacological treatment of Alzheimer disease.
Abstract

Importance  Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe and promising intervention for Alzheimer disease (AD).

Objective  To investigate the effect of a 4-week personalized hippocampal network–targeted rTMS on cognitive and functional performance, as well as functional connectivity in AD.

Design, Setting, and Participants  This randomized clinical trial, which was sham-controlled and masked to participants and evaluators, was conducted between May 2020 and April 2022 at a single Korean memory clinic. Eligible participants were between ages 55 and 90 years and had confirmed early AD with evidence of an amyloid biomarker. Participants who met the inclusion criteria were randomly assigned to receive hippocampal network–targeted rTMS or sham stimulation. Participants received 4-week rTMS treatment, with assessment conducted at weeks 4 and 8. Data were analyzed between April 2022 and January 2024.

Interventions  Each patient received 20 sessions of personalized rTMS targeting the left parietal area, functionally connected to the hippocampus, based on fMRI connectivity analysis over 4 weeks. The sham group underwent the same procedure, excluding actual magnetic stimulation. A personalized 3-dimensional printed frame to fix the TMS coil to the optimal target site was produced.

Main Outcomes and Measures  The primary outcome was the change in the AD Assessment Scale-Cognitive Subscale test (ADAS-Cog) after 8 weeks from baseline. Secondary outcomes included changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Seoul-Instrumental Activity Daily Living (S-IADL) scales, as well as resting-state fMRI connectivity between the hippocampus and cortical areas.

Results  Among 30 participants (18 in the rTMS group; 12 in the sham group) who completed the 8-week trial, the mean (SD) age was 69.8 (9.1) years; 18 (60%) were female. As the primary outcome, the change in ADAS-Cog at the eighth week was significantly different between the rTMS and sham groups (coefficient [SE], −5.2 [1.6]; P = .002). The change in CDR-SOB (−4.5 [1.4]; P = .007) and S-IADL (1.7 [0.7]; P = .004) were significantly different between the groups favoring rTMS groups. The fMRI connectivity analysis revealed that rTMS increased the functional connectivity between the hippocampus and precuneus, with its changes associated with improvements in ADAS-Cog (r = −0.57; P = .005).

Conclusions and Relevance  This randomized clinical trial demonstrated the positive effects of rTMS on cognitive and functional performance, and the plastic changes in the hippocampal-cortical network. Our results support the consideration of rTMS as a potential treatment for AD.
(more)

morganism

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Re: Parkinsons neuron degeneration halted in mice
« Reply #26 on: May 18, 2024, 12:26:32 AM »
Engineered Virus Crosses Blood-Brain Barrier to Deliver Gene Therapy

Summary: Researchers have engineered a gene therapy delivery vehicle that efficiently crosses the blood-brain barrier in mice. This breakthrough uses a human protein to ferry therapeutic genes into the brain, potentially paving the way for safer and more effective treatments for various brain diseases, including neurodevelopmental and neurodegenerative disorders.

(snip)
as their target, the researchers chose human transferrin receptor, which has long been the target of antibody-based therapies that aim to reach the brain. Several of these therapies have shown evidence of reaching the brain in humans.

The team’s screening technique identified an AAV called BI-hTFR1 that binds human transferrin receptor, enters human brain cells, and bypasses a human cell model of the blood-brain barrier.

“We’ve learned a lot from in vivo screens but it has been tough finding AAVs that worked this well across species,” added Qin Huang, a co-first author on the study and a senior research scientist in Deverman’s lab who helped develop the screening method to find AAVs that bind specific protein targets. “Finding one that works using a human receptor is a big step forward.”

Beyond the dish

To test the AAVs in animals, the researchers used mice in which the mouse gene that encodes the transferrin receptor was replaced with its human equivalent. The team injected the AAVs into the bloodstream of adult mice and found dramatically higher levels of the AAVs in the brain and spinal cord compared to mice without the human transferrin receptor gene, indicating that the receptor was actively ferrying the AAVs across the blood-brain barrier.

The AAVs also showed 40-50 times higher accumulation in brain tissue than AAV9, which is part of an FDA-approved therapy for spinal muscular atrophy in infants but is relatively inefficient at delivering cargo to the adult brain. The new AAVs reached up to 71 percent of neurons and 92 percent of astrocytes in different regions of the brain.

In work led by research scientist Jason Wu, Deverman’s team also used the AAVs to deliver healthy copies of the human GBA1 gene, which is mutated in several neurological conditions. The new AAVs delivered 30 times more copies of the GBA1 gene than AAV9 in mice and were delivered throughout the brain.

The team said that the new AAVs are ideal for gene therapy because they target a human protein and have similar production and purification yields as AAV9 using scalable manufacturing methods. A biotech company co-founded by Deverman, Apertura Gene Therapy, is already developing new therapies using the AAVs to target the central nervous system.

With more development, the scientists think it’s possible to improve the gene-delivery efficiency of their AAVs to the central nervous system, decrease their accumulation in the liver, and avoid inactivation by antibodies in some patients.

Sonia Vallabh and Eric Minikel, two researchers at the Broad who are developing treatments for prion disease, are excited by the potential of the AAVs to deliver brain therapies in humans.

“When we think about gene therapy for a whole-brain disease like prion disease, you need really systemic delivery and broad biodistribution in order to achieve anything,” said Minikel. “Naturally occurring AAVs just aren’t going to get you anywhere. This engineered capsid opens up a world of possibilities.”

https://neurosciencenews.com/aav-bbb-gene-therapy-26123/


An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery”

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across human brain endothelial cells and, relative to AAV9, provided 40–50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson’s disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9. These findings establish BI-hTFR1 as a potential vector for human CNS gene therapy.

https://www.science.org/doi/10.1126/science.adm8386