Cleveland Clinic researchers are using artificial intelligence to uncover the link between the gut microbiome and Alzheimer’s disease.
Previous studies have shown that Alzheimer’s disease patients experience changes in their gut bacteria as the disease develops. The newly published Cell Reportsstudy outlines a computational method to determine how bacterial byproducts called metabolites interact with receptors on cells and contribute to Alzheimer’s disease.
Feixiong Cheng, Ph.D., inaugural director of the Cleveland Clinic Genome Center, worked in close collaboration with the Luo Ruvo Center for Brain Health and the Center for Microbiome and Human Health (CMHH). The study ranks metabolites and receptors by the likelihood they will interact with each other, and the likelihood that the pair will influence Alzheimer’s disease. The data provide one of the most comprehensive roadmaps to studying metabolite-associated diseases to date.
Bacteria release metabolites into our systems as they break down the food we eat for energy. The metabolites then interact with and influence cells, fueling cellular processes that can be helpful or detrimental to health. In addition to Alzheimer’s disease, researchers have connected metabolites to heart disease, infertility, cancers and autoimmune disorders and allergies.
Preventing harmful interactions between metabolites and our cells could help fight disease. Researchers are working to develop drugs to activate or block metabolites from connecting with receptors on the cell surface. Progress with this approach is slow because of the sheer amount of information needed to identify a target receptor.
“Gut metabolites are the key to many physiological processes in our bodies, and for every key there is a lock for human health and disease,” said Dr. Cheng, Staff in Genomic Medicine. “The problem is that we have tens of thousands of receptors and thousands of metabolites in our system, so manually figuring out which key goes into which lock has been slow and costly. That’s why we decided to use AI.”
Dr. Cheng’s team tested whether well-known gut metabolites in the human body with existing safety profiles may offer effective prevention or even intervention approaches for Alzheimer’s disease or other complex diseases if broadly applied.
Study first author and Cheng Lab postdoctoral fellow Yunguang Qiu, Ph.D. spearheaded a team that included J. Mark Brown, Ph.D., Director of Research, CMMH; James Leverenz, MD, Director of Cleveland Clinic Luo Ruvo Center for Brain Health and Director of the Cleveland Alzheimer’s Disease Research Center; and neuropsychologist Jessica Caldwell, Ph.D., ABPP/CN. Director of the Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic Nevada.
The team used a form of AI called machine learning to analyze over 1.09 million potential metabolite-receptor pairs and predict the likelihood that each interaction contributed to Alzheimer’s disease.
The analyses integrated:
genetic and proteomic data from human and preclinical Alzheimer’s disease studies
different receptor (protein structures) and metabolite shapes
how different metabolites affect patient-derived brain cells
The team investigated the metabolite-receptor pairs with the highest likelihood of influencing Alzheimer’s disease in brain cells derived from patients with Alzheimer’s disease.
One molecule they focused on was a protective metabolite called agmatine, thought to shield brain cells from inflammation and associated damage. The study found that agmatine was most likely to interact with a receptor called CA3R in Alzheimer’s disease.
Treating Alzheimer’s-affected neurons with agmatine directly reduced CA3R levels, indicating metabolite and receptor influence each other. Treated neurons by agmatine also had lower levels of phosphorylated tau proteins, a marker for Alzheimer’s disease.
Dr. Cheng says these experiments demonstrate how his team’s AI algorithms can pave the way for new research avenues into many diseases beyond Alzheimer’s.
“We specifically focused on Alzheimer’s disease, but metabolite-receptor interactions play a role in almost every disease that involves gut microbes,” he said. “We hope that our methods can provide a framework to progress the entire field of metabolite-associated diseases and human health.”
Now, Dr. Cheng and his team are further developing and applying these AI technologies to study interactions between genetic and environmental factors (including food and gut metabolites) on human health and diseases, including Alzheimer’s disease and other complex diseases.
Summary: Researchers unveiled a novel approach to combat Alzheimer’s disease by activating microglia, the brain’s immune cells, to devour amyloid beta plaques, a hallmark of the condition. This study highlights the potential of using immunotherapy to not only tackle Alzheimer’s but also other neurodegenerative diseases characterized by harmful protein accumulations.
The team’s method involves using an antibody to stimulate microglia into clearing these plaques, offering a promising alternative to current treatments that directly target amyloid beta and might cause side effects like ARIA. This breakthrough paves the way for new therapeutic strategies that harness the immune system to fight the devastating effects of Alzheimer’s and possibly other diseases like Parkinson’s and ALS.
Key Facts:
The study introduces a groundbreaking method of activating the brain’s microglia to remove amyloid beta plaques, sidestepping the direct targeting of plaques by current Alzheimer’s drugs.
This approach has implications beyond Alzheimer’s, potentially offering a new treatment avenue for a range of neurodegenerative diseases marked by toxic protein clumps.
While existing treatments like lecanemab show promise, they carry risks such as ARIA due to the removal of amyloid from brain blood vessels; the new method presents a potentially safer alternative.
Source: WUSTL
Alzheimer’s disease starts with a sticky protein called amyloid beta that builds up into plaques in the brain, setting off a chain of events that results in brain atrophy and cognitive decline.
The new generation of Alzheimer’s drugs — the first proven to change the course of the disease — work by tagging amyloid for clearance by the brain’s immune cells.
Now, researchers at Washington University School of Medicine in St. Louis have found a different and promising way to remove the noxious plaques: by directly mobilizing immune cells to consume them.
They are working with a different mouse model — one that does have plaques on brain arteries — to understand if this new approach also carries a risk of ARIA.
In a study published April 3 in Science Translational Medicine, the researchers showed that activating immune cells called microglia with an antibody reduces amyloid plaques in the brain and mitigates behavioral abnormalities in mice with Alzheimer’s-like disease.
The approach could have implications beyond Alzheimer’s. Toxic clumps of brain proteins are features of many neurodegenerative conditions, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and Huntington’s disease.
Encouraged by the study results, researchers are exploring other potential immunotherapies – drugs that harness the immune system – to remove junk proteins from the brain that are believed to advance other diseases.
“By activating microglia generally, our antibody can remove amyloid beta plaques in mice, and it could potentially clear other damaging proteins in other neurodegenerative diseases, including Parkinson’s disease,” explained the study’s senior author, Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology.
Microglia surround plaques to create a barrier that controls the damaging protein’s spread. They also can engulf and destroy the plaque proteins, but in Alzheimer’s disease they usually do not. The source of their passivity could result from a protein called APOE that is a component of amyloid plaques.
The APOE proteins in the plaque bind to a receptor – LILRB4 – on the microglia surrounding the plaques, inactivating them, Yun Chen, co-first author on the study, explained.
For reasons that are still unknown, the researchers found that, in mice and people with Alzheimer’s disease, microglia that surround plaques produce and position LILRB4 on their cell surface, which inhibits their ability to control damaging plaque formation upon binding to APOE.
The other co-first author Jinchao Hou, PhD, now a faculty member at Children’s Hospital of Zhejiang University School of Medicine in Zhejiang Province, China, treated mice that had amyloid beta plaques in the brain with a homemade antibody that blocked APOE from binding to LILRB4.
After working with Yongjian Liu, PhD, a professor of radiology in Washington University’s Mallinckrodt Institute of Radiology, to confirm that the antibody reached the brain, the researchers found that activated microglia were able to engulf and clear the amyloid beta plaques.
Clearing the amyloid beta plaques in mice also alleviates risk-taking behavior. Individuals with AD may lack memory of past experiences to inform their decisions.
They may engage in risky behavior, making them vulnerable to becoming victims of fraud or financial abuse. Treating mice with an antibody to clear the plaques showed promise in altering the behavior.
After amyloid beta plaques form in the brain, another brain protein — tau — becomes tangled inside neurons. In this second stage of the disease, neurons die and cognitive symptoms arise. High levels of LILRB4 and APOE have been observed in AD patients in this later stage, Chen explained.
It is possible that blocking the proteins from interacting and activating microglia could alter later stages of the disease. In future studies, the researchers will test the antibody in mice with tau tangles.
Drugs that target amyloid plaques directly can cause a potentially serious side effect. In Alzheimer’s patients, amyloid proteins build up on the walls of the arteries in the brain as well as other parts of brain tissue. Removing plaques from brain blood vessels can induce swelling and bleeding, a side effect known as ARIA.
This side effect is seen in some patients receiving lecanemab, a drug approved by the Food and Drug Administration to treat Alzheimer’s. The mice used in this study lacked amyloid plaques on blood vessels, so the researchers could not evaluate what happens when blood vessel plaques are removed.
They are working with a different mouse model — one that does have plaques on brain arteries — to understand if this new approach also carries a risk of ARIA.
“Lecanemab, as the first therapeutic antibody that has been able to modify the course of the disease, confirmed the importance of amyloid beta protein in Alzheimer’s disease progression,” said author David Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology.
“And it opened new opportunities for developing other immunotherapies that use different methods of removing damaging proteins from the brain.”
The progressive neurodegenerative disease is estimated to affect 24 million people globally
Researchers from the University of British Columbia in Canada have revealed that a form of Alzheimer’s disease (AD) can be transmissible via bone marrow transplants.
Published in Stem Cell Reports, researchers believe that amyloid build-up in the brain in AD can be caused by the presence of amyloid outside of the brain.
Currently the most frequent cause of dementia, affecting an estimated 24 million people globally, AD is a brain disorder that progressively deteriorates memory and thinking skills and, eventually, the ability to carry out simple tasks.
Researchers took bone marrow cells from mice that carried a defective version of a gene linked to AD known as the amyloid precursor protein (APP) gene and transplanted them into healthy mice that lacked this genetic fault.
The APP gene plays a pivotal role in producing the APP protein found in tissues and organs, including the brain.
Following transplantation, both groups of mice were found to have developed AD, which researchers identified through symptoms of cognitive decline as well as increased levels of amyloid, a key hallmark of AD, in the brain.
In comparison, researchers found that both groups of mice developed symptoms earlier than the donor mice, which already carried the faulty APP gene.
As researchers used stem cells that had the potential to develop into blood and immune cells but not into nerve cells in the study, they suggest that amyloid build-up in the brain in AD could be triggered by the presence of amyloid outside of the brain.
Dr Chaahat Singh, first author of the study, University of British Columbia, said: “The fact that we could see significant behavioural differences and cognitive decline in the APP-knockouts at six months was surprising but also intriguing because it just showed the appearance of the disease that was being accelerated after being transferred.”
Researchers plan to test whether other types of transplants may have similar results.
A UC Davis study shows that a ketogenic diet slows early Alzheimer’s memory loss in mice through the molecule BHB, offering hope for its application in human aging and cognitive health.
A molecule found in the diet could play a significant role in slowing the progression of Alzheimer’s disease.
A recent study conducted by scientists at the University of California, Davis, reveals that a ketogenic diet can significantly delay the early stages of Alzheimer’s-related memory loss in mice. This early memory loss is comparable to mild cognitive impairment in humans that precedes full-blown Alzheimer’s disease.
The study was published in the Nature Group journal Communications Biology.
The ketogenic diet is a low-carbohydrate, high fat and moderate protein diet, which shifts the body’s metabolism from using glucose as the main fuel source to burning fat and producing ketones for energy. UC Davis researchers previously found that mice lived 13% longer on ketogenic diets.
Slowing Alzheimer’s
The new study, which follows up on that research, found that the molecule beta-hydroxybutyrate, or BHB, plays a pivotal role in preventing early memory decline. It increases almost sevenfold on the ketogenic diet.
“The data support the idea that the ketogenic diet in general, and BHB specifically, delays mild cognitive impairment and it may delay full-blown Alzheimer’s disease,” said co-corresponding author Gino Cortopassi, a biochemist and pharmacologist with the UC Davis School of Veterinary Medicine. “The data clearly don’t support the idea that this is eliminating Alzheimer’s disease entirely.”
Scientists gave mice enough BHB to simulate the benefits of being on the keto diet for seven months.
“We observed amazing abilities of BHB to improve the function of synapses, small structures that connect all nerve cells in the brain. When nerve cells are better connected, the memory problems in mild cognitive impairment are improved,” said co-corresponding author Izumi Maezawa, professor of pathology in the UC Davis School of Medicine.
Cortopassi noted that BHB is also available as a supplement for humans. He said a BHB supplement could likely support memory in mice, but that hasn’t yet been shown.
Other cognitive improvements
Researchers found that the ketogenic diet mice exhibited significant increases in the biochemical pathways related to memory formation. The keto diet also seemed to benefit females more than males and resulted in higher levels of BHB in females.
“If these results translated to humans, that could be interesting since females, especially those bearing the ApoE4 gene variant, are at significantly higher risk for Alzheimer’s,” Cortopassi said.
The research team is optimistic about the potential impact on healthy aging and plans to delve further into the subject with future studies.
Eli Lilly announced that the experimental drug donanemab showed significant benefits for early Alzheimer’s disease patients.
Beta-Amyloid Plaques and Tau in the Brain
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Alzheimer’s disease affects tens of millions of people every year, slowly stripping away cognitive function. Now, a new drug trial by Eli Lilly might be the best hope yet of slowing the inevitable progression of the disease.
The drug, donanemab, “significantly slowed cognitive and functional decline in people with early symptomatic Alzheimer’s disease,” according to an Eli Lilly statement announcing the trial results. Those patients who received the drug during the 18-month-long Phase 3 trial showed a 35% slower memory decline, cognitive function, and ability to manage common daily tasks, as measured by the integrated Alzheimer’s Disease Rating Scale (iADRS) scale, a key metric in monitoring Alzheimer’s disease progression.
“Based on these results, Lilly will proceed with global regulatory submissions as quickly as possible and anticipates making a submission to the U.S. Food and Drug Administration (FDA)…this quarter,” the company said. “Lilly will work with the FDA and other global regulators to achieve the fastest path to traditional approvals.”
The devastating effects of Alzheimer’s disease on both patients and their families are well-documented, especially given how ineffective previous attempts to slow the progression of the disease have been. With this news, Alzheimer’s sufferers and their families finally have some hope to slow the disease that once seemed as inevitable as it was unstoppable.
“Over the last 20 years, Lilly scientists have blazed new trails in the fight against Alzheimer’s disease by elucidating basic mechanisms of AD pathology and discovering imaging and blood biomarker tools to track the pathology,” Daniel Skovronsky, M.D., Ph.D., Eli Lilly’s chief scientific and medical officer, and president of Lilly Research Laboratories, said. “We are extremely pleased that donanemab yielded positive clinical results with compelling statistical significance for people with Alzheimer’s disease in this trial. This is the first Phase 3 trial of any investigational medicine for Alzheimer’s disease to deliver 35% slowing of clinical and functional decline.”
Among trial participants, nearly half (47%) of those receiving donanemab experienced no measurable worsening of symptoms after one year (measured as no decline in the sum of boxes of the clinical dementia rating, or CDR-SB), compared to 29% of participants who were on placebo. It is also noted that participants receiving the drug had a 39% lower risk of progressing to the next stage of Alzheimer’s disease compared to those on placebo,
“We are encouraged by the potential clinical benefits that donanemab may provide, although like many effective treatments for debilitating and fatal diseases, there are associated risks that may be serious and life-threatening,” Mark Mintun, M.D., group vice president of Neuroscience Research & Development at Eli Lilly and president of Avid Radiopharmaceuticals, said. “We thank the participants in the clinical trial and their loved ones for their time and commitment to finding solutions for this disease.”
Even advanced Alzheimer’s disease patients may benefit
While the most significant benefits demonstrated in the trial were for those participants in the early stages of the disease, a more limited number of advanced cases were also included in the study of donanemab, and here too there are encouraging results.
In intermediate and advanced Alzheimer’s disease cases, participants show a 29% and 22% slower progression of symptoms, respectively, so even those who have already progressed significantly into the later stages of the disease stand to benefit from the new drug.
Cautious optimism
Given how little good news there has been in the fight against Alzheimer’s disease, it is possible to overhype any progress toward a treatment. It must also be noted that this does not represent a cure for Alzheimer’s disease and that even those who respond well to the new drug are likely to experience declining cognitive functions as the disease progresses, albeit at a slower pace than before.
“It’s modest, but I think it’s real,” Dr. Ronald Petersen, an Alzheimer’s researcher at Mayo Clinic, told Reuters about the new results, “and I think it’s clinically meaningful.”
New treatments hold promise of help for the tens of millions of people suffering from Alzheimer’s disease.
New therapies may offer hope to those with Alzheimer’s disease.
Alzheimer’s is a neurodegenerative disease afflicting more than 55 million people globally.
New treatments are offering some hope for sufferers.
Here, we look at the latest research into causes and treatment options for Alzheimer’s.
Imagine forgetting how to perform simple tasks such as brushing your teeth or losing memories such as graduating college or getting married. As scary as it may sound, this is actually quite common for people with Alzheimer’s disease (AD).
According to the WHO (World Health Organization), around 55 million people worldwide are living with dementia, with the numbers expected to increase to 78 million by 2030. Out of those, around 60-70% of the cases are caused by AD. Alzheimer’s is a neurodegenerative disease, which means that it progressively causes a loss of brain cells and neural connectivity.
The disease is marked by the formation of abnormal protein deposits in the brain, which interfere with the normal functioning of the brain cells, ultimately leading to their death. The exact reason for this protein buildup is not known. However, most experts think it is caused by a combination of genetic, environmental, and lifestyle factors.
In our current understanding of this disease, it has no cure. However, there are many treatment options available that seek to manage the disease and slow its progression , and new research is being conducted every day to find a cure. Early detection and intervention can also help slow the progression of the disease and improve outcomes.
In this article, we take a look at AD in depth, how it affects the brain and its functioning, the risk factors, treatment options, and explore breakthroughs that are moving closer to finding a cure.
Symptoms and diagnosis
One of the biggest challenges with AD is its early detection, as some of the symptoms are similar to normal signs of aging, making early detection difficult. AD is typically seen in people above the age of 65, although in some cases, the symptoms can manifest earlier.
The severity of the disease varies from person to person, with some of the common symptoms including memory loss, difficulty in completing familiar tasks, disorientation, communication problems, changes in mood, decreased judgment, and personality changes.
There is no single diagnostic test for AD. Instead, doctors use a combination of neurological exams, medical history, brain imaging (including CT, PET, and MRI scans), and blood tests to make a diagnosis.
Even though much about the onset of the disease is a mystery, the buildup of proteins in the brain has been linked to neural degeneration. This includes buildup of amyloid beta, which forms senile plaques, and phosphorylated tau protein, which forms neurofibrillary tangles. This buildup generally happens in the hippocampus, which is responsible for memory storage, spatial navigation, and learning.
Risk factors
Despite our limited knowledge of the exact cause of AD, genetics is known to play a role in the development of at least some forms of the disease. The mutation of three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN 2), is known to cause a type of AD termed familial AD; and presence of one form of the polymorphic protein Apolipoprotein E (APOE) is a strong genetic risk factor for a type of AD termed sporadic AD. The mutations cause the production of abnormal proteins which are associated with AD. In addition, individuals with a genetic predisposition to AD are more likely to develop the disease than those without.
Lifestyle factors such as exercise, sleep, and diet have also been linked to risk. According to the NHS, certain risk factors associated with cardiovascular disease can also increase the risk of AD. These include smoking, obesity, high cholesterol and blood pressure, and diabetes.
However, this hesitancy does not include sleep. Sleep is required for the neural pathways in the brain to function well. Studies have shown that insomnia and sleep deprivation can lead to an accumulation of the amyloid beta protein, as well as the tau protein in the brain.
Therefore, lack of sleep can be a preventable risk factor for neurodegeneration. However, AD is a complex disease with many possible risk factors and it is not caused by lack of sleep alone.
Treatment and management
Even though AD has no known cure, there are several treatment options which can slow the progression of the disease. The treatment itself varies depending on the severity of the disease, as certain medications only work for early-stage AD.
Cholinesterase inhibitors have been shown to help to reduce or control behavioral and cognitive symptoms in early-stage AD. Their purpose is to keep acetylcholine, a neurotransmitter thought to be vital for memory, from breaking down.
Some immunotherapies, such as lecanemab and aducanumab, have also been approved by the FDA for the treatment of early-stage AD. These medications work by reducing beta-amyloid plaques in the brain.
There are also a few treatments available for people with moderate to severe AD. Memantine is a partial N-methyl-D-aspartate (NMDAR) receptor antagonist and helps some people perform day-to-day tasks for longer than they would be able to without the medicine. Scientists think it works by controlling the production of glutamate, which in large amounts can lead to brain cell death.
The FDA has also approved donepezil, which can result in a slight improvement in brain function. However, there is no evidence to suggest that donepezil alters the progression of AD.
Due to the complexity and severity of the disease, the best course of action is early detection, especially for those with a genetic predisposition to the disease. This includes regular checkups and maintaining a healthy lifestyle, with regular exercise and adequate sleep.
A few studies have also suggested cognitive behavioral therapy as a side-effect-free option for neuropsychiatric symptoms. These can help improve the quality of life for individuals with AD and their caregivers but cannot alter the progression of the disease.
Promising advances
Intriguingly, some promising new studies have the potential to point the way to a cure, or at least much more effective treatment.
A new study published in the Annals of Neurology found that suvorexant, a common insomnia medication, decreased the buildup of amyloid beta and tau proteins in the brain.
Suvorexant is a medication commonly prescribed for the treatment of insomnia. The researchers found that suvorexant decreased the concentrations of the proteins in the central nervous system. They suggest that the FDA-approved medication could be repurposed as a treatment for AD.
According to Eli Lilly, their drug donanemab slowed down the progression of AD by a third in clinical trials. Their trials showed that donanemab, given monthly, slowed the progression of Alzheimer’s by about 29% overall and helped patients’ continue more of their daily lives and activities.
However, brain swelling was seen as a common side effect, and two, and possibly three, patients in the study died as a result of its use. Future studies and trials are required to give us more information about the drug and its efficacy and side effects.
Another study, by scientists from John Hopkins University, has identified a sugar molecule the researchers call RPTPζS3L as a potential contributor to AD. RPTPζS3L binds to specific receptors in the brain, thus affecting the brain’s capacity to eliminate harmful proteins that contribute to AD.
This research could have significant consequences for the diagnosis and treatment of AD. If RPTPζS3L can be used as a diagnostic marker for AD, it would allow doctors to make a much faster diagnosis and therefore provide earlier treatment options.
Further, the discovery of this protein provides a possible target for the development of novel therapies for AD.
Conclusion
Early detection and treatment is the best way to deal with AD, especially in people who have a genetic predisposition.
The new studies and research offer a ray of hope to those going through this experience, as breakthroughs might be just around the corner.
A new link is found between Alzheimer’s transmission and discontinued treatments, shedding light on the disease’s enigma.
Alzheimer’s disease is known to be caused by an abnormal build-up of proteins in the brain cells and around it. One of the proteins involved in creating this disease is the amyloid-beta protein, as its deposits form plaques around the brain cells.
Age is a significant risk factor for Alzheimer’s as the likelihood of developing this disease doubles every five years after one hits the 65-year mark. This condition can also be inherited on rare occasions as it is sometimes genetic.
A new study by a team of UCL and UCHL researchers has provided further evidence that this condition could have also been medically acquired due to amyloid-beta protein transmission
The people described in this paper had all received treatments with a type of human growth hormone extracted from the pituitary glands of deceased individuals(cadaver-derived human growth hormone or c-hGH) at an early age. This same treatment was administered to over 1,800 people in the United Kingdom alone between 1959 and 1985.
This treatment was only withdrawn in 1985 after it was recognized that some batches of the c-hGH were contaminated with infectious proteins called prions. Surprisingly, these infectious proteins caused Creutzfeldt-Jakob disease in some people.
Some of the people who got CJD through the c-hGH treatment had prematurely developed deposits of the amyloid-beta protein in their brains as the samples of c-hGH were all contaminated with amyloid-beta.
Study finds rare cases of Alzheimer’s in middle-aged people
This new Nature Medicine paper, reported by a UCL publication, focused on eight people. These people, all of whom had been treated with c-hGH in childhood, were referred to UCLH’s National Prion Clinic at the National Hospital for Neurology and Neurosurgery in London. Five of them had symptoms of dementia, with all five of them meeting the diagnostic criteria for Alzheimer’s.
This happened despite being between 38 and 55 years old when these neurological symptoms first surfaced, proving that their symptoms are not associated with age. The team also ruled out genetic conditions as the reason behind this condition in all five people after testing their samples.
This leaves only the c-hGH treatment they had received as children as the only plausible reason for the Alzheimer’s diagnosis.
Fortunately, there are no new risks of transmitting this disease medically as the c-hGH treatment has been discontinued, and there have been no other medical procedures reported to be linked to Alzheimer’s transmission.
However, these findings have highlighted the importance of properly reviewing measures to eliminate the transmission of infectious proteins implicated in accidental transmission of CJD.
“There is no suggestion whatsoever that Alzheimer’s disease can be transmitted between individuals during activities of daily life or routine medical care. The patients we have described were given a specific and long-discontinued medical treatment, which involved injecting patients with the material now known to have been contaminated with disease-related proteins,” said the lead author of the research, Professor John Collinge, Director of the UCL Institute of Prion Diseases and a consultant neurologist at UCLH, in a press release.
Co-author Professor Jonathan Schott (UCL Queen Square Institute of Neurology, honorary consultant neurologist at UCLH, and Chief Medical Officer at Alzheimer’s Research UK) added:
“It is important to stress that the circumstances through which we believe these individuals tragically developed Alzheimer’s are highly unusual, and to reinforce that there is no risk that the disease can be spread between individuals or in routine medical care.
He noted: “These findings do, however, provide potentially valuable insights into disease mechanisms, and pave the way for further research which we hope will further our understanding of the causes of more typical, late-onset Alzheimer’s disease.”
Short, toxic RNAs kill brain cells and may allow Alzheimer’s to develop
Alzheimer’s disease, which is expected to have affected about 6.7 million patients in the U.S. in 2023, results in a substantial loss of brain cells. But the events that cause neuron death are poorly understood.
A new Northwestern Medicine study shows that RNA interference may play a key role in Alzheimer’s. For the first time, scientists have identified short strands of toxic RNAs that contribute to brain cell death and DNA damage in Alzheimer’s and aged brains. Short strands of protective RNAs are decreased during aging, the scientists report, which may allow Alzheimer’s to develop.
The study also found that older individuals with a superior memory capacity (known as SuperAgers) have higher amounts of protective short RNA strands in their brain cells. SuperAgers are individuals aged 80 and older with a memory capacity of individuals 20 to 30 years younger.
“Nobody has ever connected the activities of RNAs to Alzheimer’s,” said corresponding study author Marcus Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine. “We found that in aging brain cells, the balance between toxic and protective sRNAs shifts toward toxic ones.”
Relevance beyond Alzheimer’s disease
The Northwestern discovery may have relevance beyond Alzheimer’s. “Our data provide a new explanation for why, in almost all neurodegenerative diseases, affected individuals have decades of symptom free life and then the disease starts to set in gradually as cells lose their protection with age,” Peter said.
New avenue for treatment
The findings also point to a new way for treating Alzheimer’s and potentially other neurodegenerative diseases.
Alzheimer’s is characterized by a progressive occurrence of amyloid-beta plaques, tau neurofibrillary tangles, scarring and ultimate brain cell death.
“The overwhelming investment in Alzheimer’s drug discovery has been focused on two mechanisms: reducing amyloid plaque load in the brain — which is the hallmark of Alzheimer’s diagnosis and 70 to 80% of the effort — and preventing tau phosphorylation or tangles,” Peter said. “However, treatments aimed at reducing amyloid plaques have not yet resulted in an effective treatment that is well tolerated.
“Our data support the idea that stabilizing or increasing the amount of protective short RNAs in the brain could be an entirely new approach to halt or delay Alzheimer’s or neurodegeneration in general.”
Such drugs exist, Peter said, but they would need to be tested in animal models and improved.
The next step in Peter’s research is to determine in different animal and cellular models (as well as in brains from Alzheimer’s patients) the exact contribution of toxic sRNAs to the cell death seen in the disease and screen for better compounds that would selectively increase the level of protective sRNAs or block the action of the toxic ones.
What are toxic and protective short RNAs?
All our gene information is stored in form of DNA in the nucleus of every cell. To turn this gene information into the building blocks of life, DNA needs to be converted into RNA which is used by cell machinery to produce proteins. RNA is essential for most biological functions.
In addition to these long coding RNAs, there are large numbers of short RNAs (sRNAs), which do not code for proteins. They have other critical functions in the cell. One class of such sRNAs suppresses long coding RNAs through a process called RNA interference that results in the silencing of the proteins that the long RNAs code for.
Peter and colleagues have now identified very short sequences present in some of these sRNAs that when present can kill cells by blocking production of proteins required for cells to survive resulting in cell death. Their data suggest that these toxic sRNAs are involved in the death of neurons which contributes to the development of Alzheimer’s disease.
The toxic sRNAs are normally inhibited by protective sRNAs. One type of sRNA is called microRNAs. While microRNAs play multiple important regulatory roles in cells, they are also the main species of protective sRNAs. They are the equivalent of guards that prevent the toxic sRNAs from entering the cellular machinery that executes RNA interference. But the guards’ numbers decrease with aging, thus allowing the toxic sRNAs to damage the cells.
Key findings
The amount of protective sRNAs is reduced in the aging brain.
Adding back protective miRNAs partially protects brain cells engineered to produce less protective sRNAs from cell death induced by amyloid beta fragments (which trigger Alzheimer’s).
Enhancing the activity of the protein that increases the amount of protective microRNAs partially inhibits cell death of brain cells induced by amyloid beta fragments and completely blocks DNA damage (also seen in Alzheimer’s patients.)
How the study worked:
Scientists analyzed the brains of Alzheimer’s disease mouse models, the brains of young and old mice, induced pluripotent stem cell-derived neurons from normal individuals (both young and aged) and from Alzheimer’s patients, the brains of a group of older individuals over 80 with memory capacity equivalent to individuals 50 to 60 years old, and multiple human brain-derived neuron-like cell lines treated with amyloid beta fragments, a trigger of Alzheimer’s.
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