Alzheimer's treatment and prevention

[mr peabody]

Blocking endocannabinoids may trigger early Alzheimers

Another study from a team of investigators at the Stanford University School of Medicine led by Daniel Madison has implicated the blocking of endocannabinoids, the brains own internal versions of the active compounds in cannabis, in the early pathology of Alzheimers.

It seems a substance called A-beta, suspected to play a key role in Alzheimers because it is the main part of clumps which dot the brains of Alzheimers patients, may, in the early stages of
the disease, impair learning and memory by blocking the beneficial action of endocannabinoids.

The group at Stanford is now trying to suss out the molecular details of how this occurs. Pinning down the details could pave the path to new ways to stave off the learning disabilities and memory deficits that characterize Alzheimers and could also help explain how smoking marijuana helps to delay or even prevent its onset.

In the study, published in the June 28, 2014 issue of the scientific journal Neuron, the researchers detail how pyramidal cells in the brain underpin learning and memory. This assures, they learned, that high-intensity input such as falling down or burning your finger tends to stick in your memory, thus presumably help avoid such mishaps in the future.

Pyramidal cells are encouraged to ignore noise signals, they constantly receive random signals from upstream nerve cells by a sort of wet blanket nerve cells called interneurons.
These secret an inhibitory substance, the molecular equivalent of an indifferent shrug or yawn, signaling that the input is not really very important.

But when the news actually is significant, pyramidal cells secrete their own Now just you wait a minute, these are important chemicals. And guess what? Those chemicals which signal the importance of incoming information are none other than the endocannabinoids.

Madison speculates that when we smoke marijuana, the phytocannabinoids from the plant have the effect of enhancing the perceived importance of events that happen while we are under
the influence of pot.

And another likely effect is inhibiting the wet blanket effect of interneurons which, in Alzheimers, needs reducing to increase the ability to learn and remember.

Increasing tolerance

The federal Schedule I illegality of marijuana, under which it is officially considered to have no medical uses and a high danger of abuse, has stymied Wenk's research. But the scientist has noticed a refreshing trend, a major shift in the cultural tolerance of cannabis, particularly from young people, including his students.

Ive really seen a shift in 10 years of increased marijuana tolerance, Wenk said. In my class, people are more than willing to discuss their marijuana use. But they would be embarrassed
to mention that they smoke cigarettes.

With Alzheimers ranking as the sixth leading cause of death in the United States, and with more than five million Americans currently struggling with the disease, which has no known cure,
you would think that lab results as promising as Wenk's would have attracted major funding by now. But that is not the case, because, as we have pointed out, the NIDA is not really interested in knowing about the medical benefits of marijuana, just its dangers.

Wenk, who has researched the effects of Alzheimers on animals for about 40 years, has shared his findings in his book, Your Brain On Food.

https://tokesignals.com/marijuana-sh...ch-is-stalled/

 

[mr peabody]

The “Big Bang” of Alzheimer’s: Genesis of disease identified

Neuroscience News, July 10, 2018

Scientists have discovered a “Big Bang” of Alzheimer’s disease – the precise point at which a healthy protein becomes toxic but has not yet formed deadly tangles in the brain.

Researchers have identified the exact point at which healthy proteins become toxic in Alzheimer’s disease. The findings could help to detect Alzheimer’s before the disease progresses and develop treatments to stabilize tau proteins.

A study from UT Southwestern’s O’Donnell Brain Institute provides novel insight into the shape-shifting nature of a tau molecule just before it begins sticking to itself to form larger aggregates. The revelation offers a new strategy to detect the devastating disease before it takes hold and has spawned an effort to develop treatments that stabilize tau proteins before they shift shape.

“We think of this as the Big Bang of tau pathology. This is a way of peering to the very beginning of the disease process.”

Dr. Mark Diamond, Director for UT Southwestern’s Center for Alzheimer’s and Neurodegenerative Diseases “This is perhaps the biggest finding we have made to date, though it will likely be some time before any benefits materialize in the clinic. This changes much of how we think about the problem,” said Dr. Marc Diamond, Director for UT Southwestern’s Center for Alzheimer’s and Neurodegenerative Diseases and a leading dementia expert credited with determining that tau acts like a prion – an infectious protein that can self-replicate.

The study published in eLife contradicts the previous belief that an isolated tau protein has no distinct shape and is only harmful after it begins to assemble with other tau proteins to form the distinct tangles seen in the brains of Alzheimer’s patients.

Scientists made the discovery after extracting tau proteins from human brains and isolating them as single molecules. They found that the harmful form of tau exposes a part of itself that is normally folded inside. This exposed portion causes it to stick to other tau proteins, enabling the formation of tangles that kill neurons.

“We think of this as the Big Bang of tau pathology,” said Dr. Diamond, referring to the prevailing scientific theory about the formation of the universe. “This is a way of peering to the very beginning of the disease process. It moves us backward to a very discreet point where we see the appearance of the first molecular change that leads to neurodegeneration in Alzheimer’s. This work relied on a close collaboration with my colleague, Dr. Lukasz Joachimiak.”

Despite billions of dollars spent on clinical trials through the decades, Alzheimer’s disease remains one of the most devastating and baffling diseases in the world, affecting more than 5 million Americans alone.

Dr. Diamond is hopeful the scientific field has turned a corner, noting that identifying the genesis of the disease provides scientists a vital target in diagnosing the condition at its earliest stage, before the symptoms of memory loss and cognitive decline become apparent.

His team’s next steps are to develop a simple clinical test that examines a patient’s blood or spinal fluid to detect the first biological signs of the abnormal tau protein. "But just as important," Dr. Diamond said, "efforts are underway to develop a treatment that would make the diagnosis actionable."

Abnormal accumulations of a protein called tau can collect inside neurons, forming tangled threads—eventually
harming the synaptic connection between neurons.


He cites a compelling reason for cautious optimism: Tafamidis, a recently approved drug, stabilizes a different shape-shifting protein called transthyretin that causes deadly protein accumulation in the heart, similar to how tau overwhelms the brain.

“The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins,” Dr. Diamond said. “If it works, the incidence of Alzheimer’s disease could be substantially reduced. That would be amazing.”

Dr. Diamond’s lab, at the forefront of many notable findings relating to tau, previously determined that tau acts like a prion – an infectious protein that can spread like a virus through the brain. The lab has determined that tau protein in the human brain can form many distinct strains, or self-replicating structures, and developed methods to reproduce them in the laboratory. He said his newest research indicates that a single pathological form of tau protein may have multiple possible shapes, each associated with a different form of dementia.

https://neurosciencenews.com/alzheimers-genesis-9547/

 

[JackiePeyton]

How about learning a new language. Drugs aren't the answer

 

[Limpet_Chicken]

I disagree, at least in part. While I do think keeping the brain active and continuing to learn and use one's brain as much as possible, if there is active disease, such as dementias, one cannot just think your way to a cure, not in the sense of the afflicted individual trying to learn and keep mentally active as much as possible anyway. Not talking about research.

Do you think if my mother had just been determined enough and wanted it badly enough, that she wouldn't have ended up a near paralyzed, disgusting-smelling (its sad to say but true, she fucking stank, lying in her own shit and piss)
emptied-out husk? did she just not want to remain a human being with hopes and dreams and aspirations badly enough to have them, peyton? in the end, she just BARELY had enough left of a soul, when we had to put her into a care home, to starve herself to death, because that was the only means of hastening her own death physically possible left, to the wasted, atrophied revolting piece of hollowed out husked out vegetable matter trapping the merest occasional shorted-out sparks of thought left in her head, slobbering and hunched over like a corpse that just didn't realize it was dead yet.

Keeping mentally active is important, cells that fire together, wire together as they say.
But if an aberrant biological process is pouring poison-laden proteinaceous superglue into your brain at the molecular and cellular levels, turning your brain to fucking mush, then the answer is pharmacological intervention, targeting the specific disease process and starting it as early as genetic or protein markers in blood or saliva can be detected, and of course, testing early, development of such tests ever being pushed to the technological limits. And if any symptoms DO appear, then testing immediately, and any trace of tauopathies needs to result in immediate commencement of treatment. Because the key will be, IMO, once we can do so, to hit it hard and hit it fast. The damage that is done might be irreversible, so we need to stop it before the brain can be damaged further, stopping these diseases in their earliest manifestations, or if testing blood or saliva, or genetic testing for predisposition are developed, then even before symptoms of disease start to start attacking it pharmacologically while making sure to keep the brain active through activity is going to be vital IMO. Start fighting the disease process/es from day jack shit, the more repair efforts are directed towards the brain as it first ails,the more damage could prevented.

So drugs are the answer alright, for dealing with frank dementia-causing processes. It has to be stamped on, and HARD, with an iron-shod jackboot, as soon as possible.

 

[JackiePeyton]

Learning a foreign language has been shown to be a prevention strategy.
I am not talking about learning a language to TREAT any kind of damage. I am so sorry that you had a loved one suffer from this terrible illness. It's devastating to watch someone you love progressively lose their faculties.
I have cared for probably hundreds of folks with Alzheimers and seen first hand the damage. I have also been victim to the symptoms by being hit, bit, spit on and otherwise. I have known nurses who have had broken noses and was actually put in a choke hold by an Alzheimers patient.
Research has been close to finding a cure and no one wants this more than I do. I merely was suggesting that people who are able to and are willing to have some strategies for prevention instead of the "I'll deal with it when it comes" mentality.

 

[Coolwhip]

While I agree the post "Learn a new language. Drugs aren't the answer." Is lacking vision at best, and completely stupid at worst; I'm not going to waste my time debating with someone who thinks we shouldn't be pursuing medicinal treatments to, well, every disease.

I will say that there is quite a bit of research in on this, and while the utility of intellectual stimulation for someone whose disease has already progressed is up for debate(although I can say from my first hand experience that something as simple as daily conversations, word searches, and cross word puzzles, does miracles for helping the demented stay lucid assuming they aren't too far gone). I think you can pretty confidently say as of now it is probably the best prevention strategy we have; definitely in the top 3.

And saying "Drugs aren't the answer" is a far cry from people should adopt prevention strategies before its too late. At best you are probably talking slowing down onset and progression, and just hoping something else kills you in the mean time. Now, hoping something else kills you first, that's not an answer, while prevention is important especially when we don't have a cure, it's not really accurate in this case as we aren't preventing anything, we are delaying it, possibly delaying it until something else kills us, but still just delaying it, we need a true cure.

 

[BeachBum4u]

I recently saw where marijuana can actually protect the brain from injuries NFL football players commenly get called CTE (caused by repeated and numerous brain trauma received during competition). Oddly enough, it is a banned substance and NFL players are routinely fined and suspended for games and eventually kicked out of the league if they test positive enough times. However, I do feel eventually testing will get done, officially, and marijuana will be administered when indicated. Possibly, the NFL may even lead the charge in that direction, being they have a vested interest in protecting their players, and the "game" for that matter. I just hope testing gets done, however it gets done!

 

[Limpet_Chicken]

Peyton-yes, I too have seen all that. My mother, when it got to the point where she was still at home, but we had to have special equipment installed to move her and have carers come round once a day to change her diaper, she was a vicious little bitch to be quite honest; not few, were the times that the thing that woke me up in the morning, lying comfortably on my sofa, would be a screech of 'fucking bastard! FUCKOFF! bastard! piss off, fuck fuck fuck piss off FUCKOFF!'

Poor bastard had MS, as well as vascular dementia. I tried to offer what help I could, offers of nootropics, etc., even in the early stages were met either with refusal or outright abuse.

I still feel bad though, she ended up going into a 'care' home. Or residential facility, at least/, would be more like it, in that it was a facility, and it had residents.

She starved to death, deliberately, because it was her only way out and she was near gone. Palliative care? none. I regret it a ton, because I could have done something about it, something quick, painless and mess-free. Just wouldn't wake up one morning. But I waited too long, weighing things up.
It would have been the right thing to do, certainly, but plenty of stupid fucks out there who give a damn about the letter rather than the spirit of the law, and who are ruled by emotion rather than logic.

 

[mr peabody]

New leads on treating dementia and Alzheimer's

A new research study provides an explanation for why clinical trials of drugs reducing proteins in the brain that were thought to cause dementia and Alzheimer's have failed. The study has opened the way for potential new treatments with existing drugs.

A new research study by scientists in Australia and the US provides an explanation for why clinical trials of drugs reducing proteins in the brain that were thought to cause dementia and Alzheimer's have failed. The study has opened the way for potential new treatments with existing drugs.

Published online in the journal Human Molecular Genetics, the researchers assembled evidence from a wide range of human studies and animal models of dementia-related diseases to show that inflammation is a major cause, not just a consequence.

They show that many genes linked with dementia regulate our susceptibility and response to inflammatory damage.

"For decades, scientists have thought that dementia and Alzheimer's Disease are caused by protein aggregates forming in the brain. But recent clinical trials of drugs that reduce the aggregates have failed," says project leader Professor Robert Richards, from the University of Adelaide's School of Biological Sciences. He is working in collaboration with the University's Adelaide Medical School and the National Institutes of Health, in the US.

Inflammation has long been known to increase as dementia-related diseases progress, but only now is it identified as the cause. Previously it was thought to act simply to clean up tissue damage caused by the protein aggregates.

"We know that inflammation has different phases -- early on it can be protective against a threat by actively degrading it, but if the threat is not removed, then persistent inflammation actually causes cell death," says Professor Richards.

The new work turns previous thinking around. The genetic linkages imply that the inflammation comes first -- and the tissue damage second.

"Many genes linked with dementia operate at the level of controlling cellular inflammation. Both internal and external triggers interact with these genes to play a part. Inflammation is the point through which many triggers converge," says Professor Richards.

He likens the brain inflammation to a virus infection. "Inflammation is a very effective defence against foreign agents like viruses. But as we get older and accumulate mutations, our cells can make proteins and DNA products that mimic viruses, and these build up in the system," he says.

"Normally, our cells bar-code their own products to tell them apart from foreign agents. When these bar-codes aren't in place, our cells can't properly distinguish 'self' and 'non-self' trigger molecules. The result is inflammation that escalates and spreads -- hence the term autoinflammatory disease."

Certain types of gene mutation cause these systems to fail earlier or more often, and can increase as we age -- possibly accounting for age-related increased risk of developing dementia.

The good news is that by reducing some elements of inflammation, it may be possible to reduce dementia symptoms.

"With this new understanding of the disease, we now need to test existing anti-inflammatory drugs for their effectiveness in treating dementia," he says.

https://www.sciencedaily.com/releases/2018/05/180502104103.htm

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Alzheimer's: Molecular study clarifies potential link to high blood sugar

A new molecular study reveals for the first time that high blood sugar or glucose damages an important enzyme that is involved with how the immune system responds in the early stages of Alzheimer's disease. The researchers say the findings will help map the progression of the devastating disease to better identify those at risk and perhaps find new ways to treat or prevent it.

Abnormally high blood sugar, or hyperglycemia, is a well-known characteristic of diabetes and obesity.

However, apart from the fact that people with diabetes have a higher risk of developing Alzheimer's disease, the link between hyperglycemia and this common cause of dementia has been less clear.

Now, researchers show that macrophage migration inhibitory factor (MIF) - an enzyme that plays an important role in immune function and insulin regulation - undergoes damage associated with high glucose in early Alzheimer's disease.

The team - from the University of Bath and King's College London, both in the United Kingdom - describes the findings in a paper published in the journal Scientific Reports.

Toxic changes in the brain

Alzheimer's is a progressive brain-wasting disease that erodes people's ability to remember, think, perform daily tasks, and lead an independent life.

Among older adults, Alzheimer's disease is the most common cause of dementia, a condition that affects 46 million people worldwide.

As more studies are done, scientists are gradually unraveling the complex changes that happen in the brain during the onset and development of the disease.

Many experts believe the damage caused by Alzheimer's disease starts 10 years or more before the cognitive decline becomes apparent.

During this preclinical stage, when people appear symptom-free, toxic changes are taking place in the brain.

One of the main changes occurring in the brain is the accumulation of abnormal proteins into toxic plaques and tangles, causing once-healthy cells to stop working, lose connections with other cells, and die.

Scientists already knew that glucose and its metabolic byproducts can damage proteins through a reaction called glycation, which has also been linked to Alzheimer's disease, and is a known feature of the hyperglycemia induced by diabetes.

For the new study, the researchers used a sensitive technique to detect glycation in brain samples from people with and without Alzheimer's disease.

Sugar damage to the enzyme "MIF" could be 'tipping point'

The team found evidence that the enzyme MIF undergoes glycation damage in the early stages of the disease. It also seems that the extent of MIF glycation increases as the disease progresses.

MIF is involved in how brain cells called glia respond to the buildup of the abnormal proteins during Alzheimer's disease.

The team suggests that sugar damage to MIF reduces some of the enzyme's functions and blocks others completely, and this could be the "tipping point" that allows Alzheimer's to develop.

"We've shown that this enzyme is already modified by glucose in the brains of individuals at the early stages of Alzheimer's disease," says Jean van den Elsen, one of the senior investigators and professor in biology and biochemistry at Bath.

He and his colleagues are now investigating if they can detect similar changes in the blood.

"Excess sugar is well known to be bad for us when it comes to diabetes and obesity, but this potential link with Alzheimer's disease is yet another reason that we should be controlling our sugar intake in our diets." -Dr. Omar Kassaar

https://www.medicalnewstoday.com/ar...cpc&utm_campaign=Medical_News_Today_TrendMD_1

 

[Limpet_Chicken]

Hasn't there been already some success in examining alzheimers as a tauopathy and using antisense therapy to block aberrant Tau formation before it can misfold and send the whole scene arse over tit?

It reminds me, a lot, in it's genesis of prion diseases, universally fatal, rapid onset of dementia, massive cerebral atrophy. 'spreading like a virus' without implicating a specific viral vector is just what I'd expect from a prion. Slow, late onset, in later life, at least as long as you don't make a habit of eating people, totally lethal, and seemingly autocatalytic in its symptomatology.

It LOOKS a lot like a prion disease, like CJD, kuru (hence the eating people reference, the Fore tribe of new guinea used to practice mortuary cannibalism and the women and children got the less 'desirable' bits, and suffered more and faster than did the male adults, suffering from the shaking, wasting sickness they knew as kuru, a human-to-human prion disease, and as for amyloid beta or misfolded Tau, have either BEEN examined for potential as prion-like disease vectors?

 

[mr peabody]

^ Wo. Great post! Just ran across these...

Evidence for person-to-person transmission of Alzheimer's pathology

Study raises question about whether proteins implicated in the disease are capable of spreading through medical procedures.

Prions are the misshapen proteins that replicate by inducing normal proteins to misfold and aggregate in the brain, leading to rare diseases such as mad cow and kuru. In recent years, scientists have discovered that similar processes of protein misfolding are at work in many neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Lou Gehrig’s disease. Now, a study in Nature reveals the first evidence for human-to-human transmission of the misfolded proteins that underlie the pathology of Alzheimer’s disease.

The new findings draw upon earlier research conducted on a prion disease. Between 1958 and 1985, a number of individuals with short stature received shots of human growth hormone extracted from the pituitary glands of cadavers. The gland is a pea-sized structure that sits at the base of the brain. Some of these samples were contaminated with prions that caused certain patients to develop Creutzfeldt-Jakob disease (CJD), a rare and fatal brain disorder. Treatments ceased once these reports came to light, but by that time an estimated 30,000 people had already received the injections. As of 2012, researchers have identified 450 cases of CJD worldwide that are the result of these growth hormone injections and other medical procedures, including neurosurgery and transplants.

Misfolding of the amyloid-beta proteins is a hallmark of Alzheimer’s. Previous studies have shown that minute amounts of amyloid-beta injected into animals such as mice or monkeys act as seeds that initiate a chain reaction of protein misfolding that resembles the pathology of Alzheimer’s. However, until now, no studies have found evidence that this process occurs in humans.

To explore the question of human transmission, John Collinge, a neuroscientist at University College London and his colleagues, conducted an autopsy study of eight patients who died from CJD after treatment with cadaver-derived growth factor. To their surprise, they found that six of the brains had the amyloid-beta pathology found in Alzheimer’s patients, and four exhibited some degree of cerebral amyloid angiopathy, in which amyloid deposits build up on the walls of blood vessels in the brain.

The patients were between the ages of 36 and 51—typically too young to exhibit Alzheimer’s pathology—and none of the individuals bore genetic mutations associated with early onset of the disease. All evidence pointed toward one possibility: Like prions, amyloid-beta seeds were in the growth hormone injections and infected these individuals. Although none of the brains showed any other Alzheimer’s disease markers, such as buildup of another misfolded protein called tau, the researchers suggest that had the patients not died young, they would have developed the disease later in life.

The research may be a first step toward answering the question of whether human-to-human transmission of pathological proteins is possible. “This is an observational study,” Collinge says. “We’re simply describing what we see in these patients and we are trying to explain that.” This study alone, he says, does not suffice to prove that the Alzheimer’s disease process can be induced in one individual through contact with another’s brain tissue. In a follow-up study, the researchers are hoping to obtain archived batches of the cadaver-derived human growth hormone to look for the presence of telltale, small clusters of amyloid-beta.

One prominent Alzheimer’s investigator—John Trojanowski of the University of Pennsylvania, who was not involved in the study—asserted that the research does not provide a clear answer about whether Alzheimer’s pathology can spread between humans. Trojanowski says that the study will “generate more confused thinking and stoke unreasonable concerns by the public about the infectivity of Alzheimer’s, which I think does not help the field of prion and AD research.”

He points to the small size of the study and the fact that the subjects did not show other signs of Alzheimer’s. “Also, studies show that plaques and tangles begin to deposit as early as the second and third decade of life, which means the subjects could merely have aging-related deposition of amyloid-beta.”

But other researchers found the study to be an important contribution to the growing body of research showing that many neurodegenerative diseases may be induced through prion-like processes. All direct evidence of transmission was conducted in animal studies, Collinge says, raising questions about whether the same pathology was present in humans. “The best evidence for the transmissibility of amyloid-beta lesions comes from animal studies, in which various factors are carefully controlled and competing hypotheses are ruled out,” says Lary Walker, a neuroscientist at Emory University not involved in the study. “This study adds an important dimension to the establishment of the prion paradigm.”

Collinge emphasized that Alzheimer’s and prion diseases such as CJD cannot be “caught” through direct contact and previous epidemiological studies have found no evidence that a history of blood transfusion is associated with increased risk of Alzheimer’s disease. However, the possibility remains that certain medical procedures, such as transplants and neurosurgery, may expose individuals to amyloid-beta seeds, and the possibility of transmitting them through blood will likely become an avenue of further research.

In another study, published today in Nature Neuroscience, Mathias Jucker from the University of Tuebingen in Germany and colleagues, including Lary Walker, found that amyloid-beta seeds have the ability to persist in the brain for months and regain pathogenic properties when introduced to the right environment. Together with the evidence that Alzheimer’s pathology can be transmitted between humans, scientists are starting to look carefully at the ways in which a range of neurodegenerative diseases may develop over the course of decades—and the role that transmission between humans may play. “I think we all agree that more systematic research in this area is necessary,” says Jucker.

https://www.scientificamerican.com/article/evidence-for-person-to-person-transmission-of-alzheimer-s-pathology/

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Are prions behind all neurodegenerative diseases?

Evidence mounts that chain reactions involving toxic proteins link Creutzfeldt–Jakob disease, Alzheimer’s, Parkinson’s and more.

In the human form of mad cow disease, called Creutzfeldt-Jakob, a person's brain deteriorates—literally developing holes that cause rapidly progressing dementia. The condition is fatal within one year in 90 percent of cases. The culprits behind the disease are prions—misfolded proteins that can induce normal proteins around them to also misfold and accumulate. Scientists have known that these self-propagating, pathological proteins cause some rare brain disorders, such as kuru in Papua New Guinea. But growing evidence suggests that prions are at play in many, if not all, neurodegenerative disorders, including Alzheimer's, Huntington's and Parkinson's, also marked by aggregations of malformed proteins.

Until recently, there was no evidence that the abnormal proteins found in people who suffer from these well-known diseases could be transmitted directly from person to person. The tenor of that discussion suddenly changed this September when newly published research in the journal Nature provided the first hint such human-to-human transmission may be possible.

For the study, John Collinge, a neurologist at University College London, and his colleagues conducted autopsies on eight patients who died between the ages of 36 and 51 from Creutzfeldt-Jakob. All the subjects had acquired the disease after treatment with growth hormone later found to be contaminated with prions. The surprise came when the researchers discovered that six of the brains also bore telltale signs of Alzheimer's—in the form of clumps of beta-amyloid proteins, diagnostic for the disease—even though the patients should have been too young to exhibit such symptoms.

These observations suggest that the tainted hormone injections might have carried small amounts of beta-amyloid proteins that triggered the formation of more such proteins. Neither Alzheimer's nor any known human prion diseases are contagious through direct contact. Yet human transmission of prion diseases has occurred through certain medical procedures and, in the case of kuru, cannibalism. The new study therefore raises the possibility that Alzheimer's is a transmissible disease with an etiology akin to prion diseases.

The new finding is provocative, but experts advise caution in interpreting the results. For instance, neuroscientist John Trojanowski of the University of Pennsylvania points to the small size of the study and lack of direct evidence for transmission in support of causality. But if it is eventually shown that Alzheimer's and other neurodegenerative diseases indeed share the same basic pathological pathway and mechanism, treatments could target one and all.

“Transmission may occur in only a small percentage of human cases,” says Claudio Soto, a professor of neurology at the University of Texas Health Science Center at Houston. “But the underlying principle is the most important thing that could lead to new opportunities for therapeutic interventions and diagnostics.” Investigators such as Soto and Collinge are working on ways to detect in body fluids the presence of small clumps of the transmissible proteins now thought to be involved in Alzheimer's and other neurodegenerative diseases, which could represent a diagnostic advance.

Such detection will likely be difficult. A study published online in September in the journal Nature Neuroscience by Mathias Jucker of the University of Tuebingen in Germany and his colleagues required extremely sensitive methods to find minuscule clumps of beta-amyloid proteins, referred to as seeds, in mice brains. These seeds appear to be able to regain pathological properties even after six months of lying dormant. These possibly prion-like proteins might therefore exist in the brain long before symptoms develop, at levels too low to be found by routine tests.

One potentially prionlike protein may cause several diseases, according to a study published this summer by Nobel laureate Stanley Prusiner, who discovered prions in the 1980s. Prusiner and his colleagues found that a “strain” of alpha-synuclein—the misfolded protein involved in Parkinson's—can cause a similar but rare neurodegenerative disease, called multiple-system atrophy. Understanding how variants of these disease-causing proteins differ in shape and how the particular configuration influences their pathogenic nature is destined to become a focus of future research. “There's evidence that both prions and beta-amyloid exist as different strains and have very different biological effects,” says Lary C. Walker of Emory University, who was involved in the Nature Neuroscience study. “I think understanding this will give us insight into what's happening in disease.”

As the evidence increases, more scientists now suspect that prion-like processes probably underlie all neurodegenerative disorders. Prusiner expected the current change in thinking: in his 1997 Nobel Prize lecture, he predicted that "the understanding of prion formation could open new approaches to deciphering the causes of and to developing effective therapies for the more common neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).”

https://www.scientificamerican.com/article/are-prions-behind-all-neurodegenerative-diseases1/

 

[Limpet_Chicken]

I don't know as Huntington's could be described as a prion like disease. It does involve screwed up proteins, with familial extension over generations of a CAG repeat within the gene of the protein known as huntingtin, below a certain length of these CAG nucleotide sequence repeats, it renders one more and more likely to become a carrier, with a generation, the longer the repeat of repeats of the CAG nucleotide repeat, the more severe eventual disease, and after a certain number of CAG repeats, Huntington's disease will manifest. I don't think its prion like, exactly, certainly genetic, although whether the protein itself is ALL misfolded, some is and some is not, and the balance being the important factor in eventual disease pathology, I am uncertain. I don't know whether the mutant huntingtin acts as an autocatalytic poison, causing exponential swarming of the misfolded proteins, with good huntingtin caused to misfold (I.e whether one could without altering gene expression, for example, inject someone in the brain with mutant, pathological huntingtin in an individual who themselves had a normal length and composition of the huntingtin gene sequence and then their come down with Huntington's disease, like with Kuru being transferred I don't know)

Although my advice to people in general would be not to go round eating people, and particularly not sucking the brains and spinal cords out of old people and the diseased. Just as a general principle, if you are going to practice cannibalism, do your background research, get some surreptitious genetic testing done and make sure they are free of alzheimer's-prone biomarkers etc. before you start chopping up your pensioners for tonight's chili con carne.

You are who you eat, so eat healthy. Kill a vegan today

Edit-the nucleotide triplet CAG encodes glutamine. There are, I believe a number of these polyglutamine tract repeat neurological diseases. And now it is possible to test for certain of them, such as whether one is going to develop Huntington's disease, or if they have carrier status.

 

[mr peabody]

Cannabis compound removes toxic Alzheimer's protein from the brain

THC has been found to promote the removal of toxic clumps of amyloid beta protein in the brain, which are thought to kickstart the progression of Alzheimer's disease.

The finding supports the results of previous studies that found evidence of the protective effects of cannabinoids, including THC, on patients with neurodegenerative disease.

"Although other studies have offered evidence that cannabinoids might be neuroprotective against the symptoms of Alzheimer's, we believe our study is the first to demonstrate that cannabinoids affect both inflammation and amyloid beta accumulation in nerve cells," says one of the team, David Schubert from the Salk Institute for Biological Studies in California.

Schubert and his colleagues tested the effects of THC on human neurons grown in the lab that mimic the effects of Alzheimer's disease.

If you're not familiar with this special little compound, it's not only responsible for the majority of marijuana's psychological effects - including the high - thanks to its natural pain-relieving properties, it's also been touted as an effective treatment for the symptoms of everything from HIV and chemotherapy to chronic pain, post traumatic stress disorder, and stroke.

In fact, THC appears to be such an amazing medical agent, researchers are working on breeding genetically modified yeast that can produce it way more efficiently than it would be to make synthetic versions.

The compound works by passing from the lungs to the bloodstream, where it attaches to two types of receptors, cannabinoid receptor (CB) 1 and 2, which are found on cell surfaces all over the body.

In the brain, these receptors are most concentrated in neurons associated with pleasure, memory, thinking, coordination and time perception, and usually bind with a class of lipid molecules called endocannabinoids that are produced by the body during physical activity to promote cell-to-cell signalling in the brain.

But THC can also bind to them in much the same way, and when they do, they start messing with your brain's ability to communicate with itself.

Over the years, research has suggested that by binding to these receptors, THC could be having another effect on ageing brains, because it appears to helps the body clear out the toxic accumulations - or 'plaques' - of amyloid beta.

No one's entirely sure what causes Alzheimer's disease, but it's thought to result from a build-up of two types of lesions: amyloid plaques and neurofibrillary tangles.

Amyloid plaques sit between the neurons as dense clusters of beta-amyloid molecules - a sticky type of protein that clumps together - and neurofibrillary tangles are caused by defective tau proteins that clump up into a thick, insoluble mass in the neurons.

It's not clear why these lesions begin to appear in the brain, but studies have linked inflammation in the brain tissue to the proliferation of plaques and neurofibrillary tangles. So if we can find something that eases brain inflammation while at the same time encourages the body to clear out these lesions, we could be on the way to finding the first effective treatment for Alzheimer's ever.

In 2006, researchers at the Scripps Research Institute found that THC inhibits the formation of amyloid plaques by blocking the enzyme in the brain that produces them, and now Schubert and his team have demonstrated that it can also eliminate a dangerous inflammatory response from the nerve cells, ensuring their survival.

"Inflammation within the brain is a major component of the damage associated with Alzheimer's disease, but it has always been assumed that this response was coming from immune-like cells in the brain, not the nerve cells themselves," says one of the team, Antonio Currais.

"When we were able to identify the molecular basis of the inflammatory response to amyloid beta, it became clear that THC-like compounds that the nerve cells make themselves may be involved in protecting the cells from dying."

It's exciting stuff, but so far it has only been demonstrated in neurons in the lab, so the next step will be for Schubert and his team to observe the link between THC and reduced inflammation and plaque build-up in a clinical trial.

They've reportedly already found a drug candidate called J147 that appears to have the same effects as THC, so this might be the way they can test the effects of THC without the government getting in the way.

Though it's worth adding that more recent legal changes since the time of this research around marijuana use in the USA may be making further research in this area a lot easier.

https://www.sciencealert.com/marijuana-compound-thc-removes-toxic-alzheimer-protein-from-brain

 

[Limpet_Chicken]

How does the fact that SOLUBLE amyloid-beta also appears neurotoxic, to the reduction in tangles and of course the wellknown tauopathy in ALZH ?

 

[Weltmeister]

Doesnt seem like alzheimer researchers themselves have a very deep understanding on what exactly is happening.

Despite the vast amount of information gathered for more than the last 30 years on the pathogenesis of AD, the track record for compounds targeting the amyloid pathway is abysmal with no single Phase III trial reporting a positive result on a primary outcome [9]. The extensive number of studies (clinical and preclinical) related to Aβ notwithstanding fundamental questions [10] critical to the success of clinical trials such as the actual toxicity of the peptide remains unanswered or poorly understood [11].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651424/

Since 1992, the amyloid cascade hypothesis has played the prominent role in explaining the etiology and pathogenesis of Alzheimer's disease (AD). It proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs), neuronal cell death, and ultimately dementia. While there is substantial evidence supporting the hypothesis, there are also limitations: (1) SP and NFT may develop independently, and (2) SPs and NFTs may be the products rather than the causes of neurodegeneration in AD. In addition, randomized clinical trials that tested drugs or antibodies targeting components of the amyloid pathway have been inconclusive.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313573/

 

[sekio]

[insert: cartoon gnomes in white lab coats stare at a whiteboard:
1. Amyloid-beta plaque deposition
2. ???
3. Profit! Cell mortality]

 

[mr peabody]

Alzheimer's link to herpes virus in the brain, say scientists

Research reveals strains of virus more abundant in brains with early stage of disease, though uncertainly whether virus is a trigger or a symptom.

The presence of viruses in the brain has been linked to Alzheimer’s disease in research that challenges conventional theories about the onset of dementia.

The results, based on tests of brain tissue from nearly 1,000 people, found that two strains of herpes virus were far more abundant in the brains of those with early-stage Alzheimer’s than in healthy controls. However, scientists are divided on whether viruses are likely to be an active trigger, or whether the brains of people already on the path towards Alzheimer’s are simply more vulnerable to infection.

“The viral genomes were detectable in about 30% of Alzheimer’s brains and virtually undetectable in the control group,” said Sam Gandy, professor of neurology at the Icahn School of Medicine at Mount Sinai, New York and a co-author of the study.

The study also suggested that the presence of the herpes viruses in the brain could influence or control the activity of various genes linked to an increased risk of Alzheimer’s.

The scientists did not set out to look for a link between viruses and dementia. Instead they were hoping to pinpoint genes that were unusually active in the brains of people with the earliest stage of Alzheimer’s. But when they studied brain tissue, comparing people with early-stage Alzheimer’s and healthy controls, the most striking differences in gene activity were not found in human genes, but in genes belonging to two herpes virus strains, HHV6A and HHV7. And the abundance of the viruses correlated with clinical dementia scores of the donors.

“We didn’t go looking for viruses, but viruses sort of screamed out at us,” said Ben Readhead, assistant professor at Arizona State University-Banner Neurodegenerative Disease Research Center and lead author.

Gandy said the team were initially “surprised and sceptical” about the results, based on brain tissue from the Mount Sinai Brain bank, and so repeated the study using two further brain banks – in total 622 brains with signs of Alzheimer’s and 322 healthy control brains – and detected the very same genes. “We’ve tried to be conservative in our interpretation and replicated the results in three different brain banks, but we have to at least recognise that these diseased brains are carrying these viral genomes,” he added.

The scientists could not prove whether viruses actively contribute to the onset of disease, but they discovered a plausible mechanism for how this could happen. Some of the herpes genes were found to be boosting the activity of several known Alzheimer’s genes.

David Reynolds, chief scientific officer of Alzheimer’s Research UK, said this element was significant. “Previous studies have suggested that viruses might be linked with Alzheimer’s, but this detailed analysis of human brain tissue takes this research further, indicating a relationship between the viruses and the activity of genes involved in Alzheimer’s, as well as brain changes, molecular signals, and symptoms associated with the disease,” he said.

However, others were more sceptical. Prof John Hardy, a geneticist at University College London, said: “There are some families with mutations in specific genes who always get this disease. It’s difficult to square that with a viral aetiology. I’d urge an extremely cautious interpretation of these results.”

The viruses highlighted are not the same as those that cause cold sores, but much more common forms of herpes that nearly everyone carries and which don’t typically cause any problems. The study in no way suggests that Alzheimer’s disease is contagious or can be passed from person to person like a virus – or that having cold sores increases a person’s risk of dementia.

There are currently 850,000 people living with dementia in Britain, and the number is projected to rise to a million by 2025 and 2 million by 2050. But despite hundreds of drug trials during the past decade, an effective treatment has not yet emerged.

“While these findings do potentially open the door for new treatment options to explore in a disease where we’ve had hundreds of failed trials, they don’t change anything that we know about the risk and susceptibility of Alzheimer’s disease or our ability to treat it today,” said Gandy.

https://www.theguardian.com/society/2018/jun/21/alzheimers-link-to-herpes-virus-in-brain-say-scientists

 

[mr peabody]

Ayahuasca stimulates brain cells and could treat Alzheimer’s

By Olivia Lerche

SCIENTISTS have discovered that a hallucinogenic substance from the Amazon stimulates the birth of new brains cells and could lead to treatment for neurodegenerative diseases such as Alzheimer’s disease. The tea called Ayahuasca, is also used as a traditional spiritual medicine in ceremonies in Peru, South America.

The Sant Pau Hospital Barcelona, which worked in collaboration with the Beckley Foundation and Spanish National Research Council in Madrid, has released the findings from a study investigating the potential of ayahuasca to promote neurogenesis - which is the development of new brain cells. The investigators believe that these findings will open up a new avenue of research that may help develop drugs to treat diseases like Alzheimer’s, Parkinson’s and addiction.

Dr Jordi Riba, lead investigator, presented preliminary data, at the Interdisciplinary Conference on Psychedelic Research in Amsterdam at the weekend. Results showed that two compounds - harmine and tetrahydro harmine - which are found in the hallucinogenic tea, potently stimulated the transformation of stem cells into new neurons.

Amanda Feilding, director of the Beckley Foundation said: “The images from the Beckley/Sant Pau collaboration showing the birth of new neurons are very interesting and suggest that ayahuasca could lead to a new approach in the treatment of neurodegenerative conditions such as Alzheimer’s and Parkinson’s, among others.”

Experts have believed for years that the brain doesn’t make neurons during adulthood. In the 1990s, research changed this finding, showing that new neurons are generated throughout adult life in two regions of the human brain: the area around the ventricles and in the hippocampus. The hippocampus, thought to be the center of emotion and autonomic nervous system, plays a key role in memory. Its function declines with age and in neurological disorders.

Under normal conditions, the rate of the birth of new neurons is very low, and it cannot keep up with the rate of neural death that occurs in diseases such such as Alzheimer’s disease. In the study, neural stem cells were isolated from the hippocampus of adult mice. The stem cells were grown in the lab and substances that are present in ayahuasca were added to the cultures and compared with saline a placebo control.

Scientists have described the results as ‘impressive’, with ayahuasca substances stimulating the transformation of stem cells into new neurons.

Dr Riba has been studying ayahuasca for twenty years.

 

[mr peabody]

Vicious circle leads to loss of brain cells in old age: THC may help reverse the process

The so-called CB1 receptor is responsible for the intoxicating effect of cannabis. However, it appears to act also as a kind of “sensor” with which neurons measure and control the activity of certain immune cells in the brain. A recent study by the University of Bonn at least points in this direction. If the sensor fails, chronic inflammation may result – probably the beginning of a dangerous vicious circle. The publication appears in the journal Frontiers in Molecular Neuroscience.

The activity of the so-called microglial cells plays an important role in brain aging. These cells are part of the brain’s immune defense: For example, they detect and digest bacteria, but also eliminate diseased or defective nerve cells. They also use messenger substances to alert other defense cells and thus initiate a concerted campaign to protect the brain: an inflammation.

This protective mechanism has undesirable side effects; it can also cause damage to healthy brain tissue. Inflammations are therefore usually strictly controlled. “We know that so-called endocannabinoids play an important role in this”, explains Dr. Andras Bilkei-Gorzo from the Institute of Molecular Psychiatry at the University of Bonn. “These are messenger substances produced by the body that act as a kind of brake signal: They prevent the inflammatory activity of the glial cells.”

Endocannabinoids develop their effect by binding to special receptors. There are two different types, called CB1 and CB2. “However, microglial cells have virtually no CB1 and very low level of CB2 receptors,” emphasizes Bilkei-Gorzo. “They are therefore deaf on the CB1 ear. And yet they react to the corresponding brake signals – why this is the case, has been puzzling so far.”

Neurons as “middlemen”

The scientists at the University of Bonn have now been able to shed light on this puzzle. Their findings indicate that the brake signals do not communicate directly with the glial cells, but via middlemen – a certain group of neurons, because this group has a large number of CB1 receptors. “We have studied laboratory mice in which the receptor in these neurons was switched off,” explains Bilkei-Gorzo. “The inflammatory activity of the microglial cells was permanently increased in these animals.”

In contrast, in control mice with functional CB1 receptors, the brain’s own defense forces were normally inactive. This only changed in the present of inflammatory stimulus. “Based on our results, we assume that CB1 receptors on neurons control the activity of microglial cells,” said Bilkei-Gorzo. “However, we cannot yet say whether this is also the case in humans.”

This is how it might work in mice: As soon as microglial cells detect a bacterial attack or neuronal damage, they switch to inflammation mode. They produce endocannabinoids, which activate the CB1 receptor of the neurons in their vicinity. This way, they inform the nerve cells about their presence and activity. The neurons may then be able to limit the immune response. The scientists were able to show that neurons are similarly regulatory for the other major glial cell type, the astroglial cells.

During ageing the production of cannabinoids declines reaching a low level in old individuals. This could lead to a kind of vicious circle, Bilkei-Gorzo suspects: “Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode. More regulatory neurons die as a result, so the immune response is less regulated and may become free-running.”

It may be possible to break this vicious circle with drugs in the future. It is for instance hoped that cannabis will help slow the progression of dementia. Its ingredient, tetrahydrocannabinol (THC), is a powerful CB1 receptor activator – even in low doses free from intoxicating effect. Last year, the researchers from Bonn and colleagues from Israel were able to demonstrate that cannabis can reverse the aging processes in the brains of mice. This result now suggest that an anti-inflammatory effect of THC may play a role in its positive effect on the ageing brain.

https://neurosciencenews.com/apoptosis-aging-9783/

 

[mr peabody]

In vivo evidence of therapeutic properties of CBD for Alzheimer's Disease

A review and summary of animal subject studies of CBD in relation to neuroprotective effects and Alzheimer's disease. The studies demonstrate the ability of CBD to reduce the change caused by damage to neural cells and reduce the neuroinflammatory response. CBD was also shown to promote neurogenesis. Importantly, CBD also reverses and prevents the development of cognitive deficits in Alzheimer's rodent models. Interestingly, combination therapies (of CBD and THC) showed that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289988/

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CBD modulates the expression of Alzheimer's Disease-related genes

Stem cells, mesenchymal stem cells to be exact, have emerged as a promising tool for the treatment of neurodegenerative disorders, including Alzheimer's disease. Current therapies for Alzheimer's that utilize mesenchymal stem cells have shown limited effectiveness. This study evaluates whether pre-treatment with cannabidiol modulates mesenchymal stem cells in order to improve their therapeutic potential. The results showed that pre-treatment with CBD prevented the expression of proteins and suggested that mesenchymal stem cells preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of Alzheimer's.

https://www.ncbi.nlm.nih.gov/pubmed/28025562

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Safety and efficacy of CBD for behavioral and psychological symptoms of Dementia

With a given premise of THC as a potential treatment for Alzheimer's, this clinical trial looked at whether CBD oil was effective in relieving behavioral and psychological symptoms of dementia. CBD oil was given in addition pharmaceutical drugs already prescribed for this group of 11 trial participants. The trial lasted for 4 weeks. Results showed that delusions, agitation/aggression, irritability, apathy, sleep distress and caregiver distress were all reduced.

https://www.ncbi.nlm.nih.gov/pubmed/26757043

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Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer's Disease

Utilizing the endocannabinoid system and synthetic cannabinoids for the modulation of neuroinflammation that is related to Alzheimer's disease was a given for this review. They looked at many studies, case studies and trials. Findings from 6 studies showed significant benefits from synthetic cannabinoids, specifically dronabinol and nabilone. It was noted that conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies.

https://www.ncbi.nlm.nih.gov/pubmed/26271310

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CBD and other cannabinoids reduce Microglial Activation in Alzheimer's Disease

This study suggests that microglial activity has been shown as a feature of Alzheimer's disease. In the present study, they compared the effects of cannbidiol with those of other cannabinoids on microglial cell functions, learning behavior and cytokine expression after beta amyloid administration in mice. The study found that CBD was able to modulate microglial activity, and produce beneficial effects in animal subjects model of Alzheimer's.

https://www.ncbi.nlm.nih.gov/pubmed/21350020

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CBD in vivo blunts Meta-amyloid-induced Neuroinflammation

To confirm the results of a previous study showing that cannabidiol inhibited gliosis in vivo in mice, mice were inoculated with human peptide into the right dorsal hippocampus, and treated daily with CBD and a non-CBD substance for 7 days. The dosage of CBD used was 2.5 or 10 mg per kg of body weight. CBD significantly inhibited markers of neuroinflammation in the animal subjects. This was also dose dependent. The results of this study confirm the in vivo anti-inflammatory actions of CBD.

https://www.ncbi.nlm.nih.gov/pubmed/17592514

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Neuroprotective effect of CBD on Beta-amyloid-induced toxicity in PC12 cells

This study looked at the effect of cannabidiol on peptide toxicity in rat cells in culture. The toxic effect was increased reactive oxygen species, lipid peroxidation, cell death signaling cascade, increased intracellular calcium, and DNA fragmentation. Treatment of the cells with cannabidiol prior to toxic peptide exposure significantly elevated cell survival while it decreased reactive oxygen species production, lipid peroxidation, cell death signaling levels, DNA fragmentation and intracellular calcium. Results indicated that CBD exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic (anti cell death) effects against peptide toxicity.

https://www.ncbi.nlm.nih.gov/pubmed/15030397

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CBD reverses deficits in Hippocampal LTP in a model of Alzheimer's Disease

Synaptic plasticity protection by cannabidiol is demonstrated for the first time in an in vitro model. The study looked at the effect of CBD on amyloid peptides. Amyloid peptides are known to reduce persistent increase in synaptic strength in the hippocampus part of the brain. CBD alone did not alter persistent increase in synaptic strength in the hippocampus. But, pre-treatment with CBD protected the persistent increase in synaptic strength. Essentially, CBD protected the hippocampus and memory from the peptide that is known to cause Alzheimer's disease.

https://www.ncbi.nlm.nih.gov/pubmed/29574668