Category: Neurodegenerative Diseases

Categories : Neurodegenerative DiseasesTags :

Alzheimer’s Disease may Damage the Brain in Two Phases

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Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH

Alzheimer’s disease may damage the brain in two distinct phases, based on new research funded by the National Institutes of Health (NIH) using sophisticated brain mapping tools. According to researchers who discovered this new view, the first, early phase happens slowly and silently – before people experience memory problems – harming just a few vulnerable cell types. In contrast, the second, late phase causes damage that is more widely destructive and coincides with the appearance of symptoms and the rapid accumulation of plaques, tangles, and other Alzheimer’s hallmarks.

“One of the challenges to diagnosing and treating Alzheimer’s is that much of the damage to the brain happens well before symptoms occur. The ability to detect these early changes means that, for the first time, we can see what is happening to a person’s brain during the earliest periods of the disease,” said Richard J. Hodes, MD, director, NIH National Institute on Aging. “The results fundamentally alter scientists’ understanding of how Alzheimer’s harms the brain and will guide the development of new treatments for this devastating disorder.”

Scientists analysed the brains of 84 people, and the results, published in Nature Neuroscience, suggest that damage to one type of cell, called an inhibitory neuron, during the early phase may trigger the neural circuit problems that underlie the disease. Additionally, the study confirmed previous findings about how Alzheimer’s damages the brain and identified many new changes that may happen during the disease.

Specifically, the scientists used advanced genetic analysis tools to study the cells of the middle temporal gyrus, a part of the brain that controls language, memory and vision. The gyrus has been shown to be vulnerable to many of the changes traditionally seen during Alzheimer’s. It is also a part of the brain that researchers have thoroughly mapped for control donors. By comparing control donor data with that from people who had Alzheimer’s, the scientists created a genetic and cellular timeline of what happens throughout the disease.

Traditionally, studies have suggested that the damage caused by Alzheimer’s happens in several stages characterized by increasing levels of cell death, inflammation and the accumulation of proteins in the form of plaques and tangles. In contrast, this study suggests that the disease changes the brain in two “epochs” – or phases – with many of the traditionally studied changes happening rapidly during the second phase. This coincides with the appearance of memory problems and other symptoms.

The results also suggest that the earliest changes happen gradually and “quietly” in the first phase before any symptoms appear. These changes include slow accumulation of plaques, activation of the brain’s immune system, damage to the cellular insulation that helps neurons send signals and the death of cells called somatostatin (SST) inhibitory neurons.

The last finding was surprising to the researchers. Traditionally, scientists have thought that Alzheimer’s primarily damages excitatory neurons, which send activating neural signals to other cells. Inhibitory neurons send calming signals to other cells. The paper’s authors hypothesised how loss of SST inhibitory neurons might trigger the changes to the brain’s neural circuitry that underlie the disease.

Recently, a separate NIH-funded brain mapping study by researchers at MIT found that a gene called REELIN may be associated with the vulnerability of some neurons to Alzheimer’s. It also showed that star-shaped brain cells called astrocytes may provide resilience to or resist the harm caused by the disease.

Researchers analysed brains that are part of the Seattle Alzheimer’s Disease Brain Cell Atlas, which is designed to create a highly detailed map of the brain damage that occurs during the disease. The project was led by Mariano I. Gabitto, PhD, and Kyle J. Travaglini, PhD, from the Allen Institute, Seattle. The scientists used tools – developed as part of the NIH’s BRAIN Initiative – Cell Census Network – to study more than 3.4 million brain cells from donors who died at various stages of Alzheimer’s disease.

“This research demonstrates how powerful new technologies provided by the NIH’s BRAIN Initiative are changing the way we understand diseases like Alzheimer’s. With these tools, scientists were able to detect the earliest cellular changes to the brain to create a more complete picture of what happens over the entire course of the disease,” said John Ngai, Ph.D., director of The BRAIN Initiative®. “The new knowledge provided by this study may help scientists and drug developers around the world develop diagnostics and treatments targeted to specific stages of Alzheimer’s and other dementias.”

Source: NIH/National Institute on Aging

Categories : Cancer Neurodegenerative DiseasesTags :

MS Associated with an Increased Risk of Certain Cancers

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This is a pseudo-coloured image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.

Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

A new study has found some cancers to be slightly more frequent in people with multiple sclerosis (MS) than in people without MS. The study is published online in Neurology®, the medical journal of the American Academy of Neurology. Types of cancers found to have a small increased risk include bladder, brain and cervical cancers.

“People with MS undergo an increased number of tests to monitor MS, making it more likely to detect other diseases,” said study author Emmanuelle Leray, PhD, of Rennes University in France. “We found an association between some types of cancer and MS which may have different explanations depending on a person’s age and the types of cancer. Overall, our study found the increased risk of cancer was quite small.”

For the study, researchers reviewed 10 years of data in the French national health care database. Researchers identified 140 649 people with MS and matched them for factors such as age, sex and residence to 562 596 people without MS. All participants were cancer free three years before the study. They were followed for an average of eight years.

During the study, 8,368 people with MS and 31,796 people without MS developed cancer.

Researchers determined there were 799 cancers per 100 000 person-years for people with MS and 736 cancers per 100 000 person-years for people without MS. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

Researchers found people with MS had a 6% increased risk of developing any type of cancer regardless of age, sex and residence. They also found cancer risk was higher in those under 55 and lower in people 65 and older when compared to people without MS.

Researchers then looked at cancer types. People with MS had a 71% increased risk for bladder cancer, a 68% increased risk for brain cancer and a 24% increased risk for cervical cancer. However, they also had a 20% lower risk of prostate cancer, a 10% lower risk of colorectal cancer and a 9% lower risk of breast cancer.

“While our study found a higher risk for brain cancer, it may be due in part to earlier detection in those with MS since they regularly have brain scans which may detect cancers earlier, before a person has symptoms,” said Leray. “Frequent urinary tract infections in people with MS and the use of immunosuppressant drugs may contribute to their higher risk of bladder and cervical cancers.”

Leray added, “The lower risk for colorectal and breast cancers may be due in part to fewer people with MS getting screened for cancer in older age when they may be experiencing more MS symptoms. More research is needed, including studies that look at more closely at how cancer screenings may play a role.”

A limitation of the study was that researchers were unable to adjust for factors such as education, income, smoking and alcohol consumption since this information was not available in the national database.

Source: American Academy of Neurology

Categories : Immune System Neurodegenerative DiseasesTags :

New Approach to MS ‘Teaches’ Immune Cells not to Attack

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Myelin sheath damage. Credit: Scientific Animations CC4.0

Researchers from have found a potential new way to improve the treatment of multiple sclerosis (MS) using a novel combined therapy. The results, published in the Journal of Clinical Investigation, builds on two harmonised Phase I clinical trials, focusing on the use of Vitamin D3 tolerogenic dendritic cells (VitD3-tolDCs) to regulate the immune response in MS patient.

Multiple Sclerosis (MS) is a long-term disease where the immune system mistakenly attacks the protective myelin sheath around nerve cells. This leads to nerve damage and worsening disability. Current treatments, like immunosuppressants, help reduce these harmful attacks but also weaken the overall immune system, leaving patients vulnerable to infections and cancer. Scientists are now exploring a more targeted therapy using special immune cells, called tolerogenic dendritic cells (tolDCs), from the same patients.

TolDCs can restore immune balance without affecting the body’s natural defences. However, since a hallmark of MS is precisely the dysfunction of the immune system, the effectiveness of these cells for auto transplantation might be compromised. Therefore, it is essential to better understand how the disease affects the starting material for this cellular therapy before it can be applied.

In this study, researchers from Barcelona’s Germans Trias i Pujol Institute and Josep Carreras Leukaemia Research Institute, examined CD14+ monocytes, mature dendritic cells (mDCs), and Vitamin D3-treated tolerogenic dendritic cells (VitD3-tolDCs) from MS patients who had not yet received treatment, as well as from healthy individuals. The clinical trials (NCT02618902 and NCT02903537) are designed to assess the effectiveness of VitD3-tolDCs, which are loaded with myelin antigens to help “teach” the immune system to stop attacking the nervous system. This approach is groundbreaking as it uses a patient’s own immune cells, modified to induce immune tolerance, in an effort to treat the autoimmune nature of MS.

The study, led by Dr Eva Martinez-Cáceres and Dr Esteban Ballestar, with Federico Fondelli as first author, found that the immune cells from MS patients (monocytes, precursors of tolDCs) have a persistent “pro-inflammatory” signature, even after being transformed into VitD3-tolDCs, the actual therapeutic cell type. This signature makes these cells less effective compared to those derived from healthy individuals, missing part of its potential benefits.

Using state-of-the-art research methodologies, the researchers identified a pathway, known as the Aryl Hydrocarbon Receptor (AhR), that is linked to this altered immune response. By using an AhR-modulating drug, the team was able to restore the normal function of VitD3-tolDCs from MS patients, in vitro. Interestingly, Dimethyl Fumarate, an already approved MS drug, was found to mimic the effect of AhR modulation and restore the cells’ full efficacy, with a safer toxic profile.

Finally, studies in MS animal models showed that a combination of VitD3-tolDCs and Dimethyl Fumarate led to better results than using either treatment on its own. This combination therapy significantly reduced symptoms in mice, suggesting enhanced potential for treating human patients.

These results could lead to a new, more potent treatment option for multiple sclerosis, offering hope to the millions of patients worldwide who suffer from this debilitating disease. This study represents a significant step forward in the use of personalised cell therapies for autoimmune diseases, potentially revolutionising how multiple sclerosis is treated.

The team is now preparing to move into Phase II trials to further explore these findings.

Source: Josep Carreras Leukaemia Research Institute

Categories : Ethics and Law Neurodegenerative DiseasesTags :

Over 100 Key Alzheimer’s Papers Found To Have Suspicious Data

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Photo by National Cancer Institute on Unsplash

An investigation by Science has shown that over 100 key papers on Alzheimer’s research have used falsified data. The papers all have a common author – veteran neuropathologist Eliezer Masliah, a key researcher at the National Institute on Aging (NIA), typically as first or last author.

The investigation has found that scores of Masliah’s lab studies at the University of California San Diego (UCSD) and NIA are riddled with apparently falsified Western blots (images used to show the presence of proteins) and micrographs of brain tissue. Numerous images seem to have been inappropriately reused within and across papers, sometimes published years apart in different journals, under supposedly different experimental conditions.

At UCSD, Masliah had amassed decades of experience researching Alzheimer’s and Parkinson’s disease, amassing 800 papers. Some important topics in them, such as alpha-synuclein (a protein linked to both diseases), continue to have great influence. The US Congress had released a flood of funding for Alzheimer’s research, US$2.6 billion for last year’s budget, far outstripping that for the rest of the NIA, and Masliah was an ideal choice for its neuroscience division director. This was a position which was enormously influential for Alzheimer’s research in the US as well as internationally, allowing him to fund selected research over and above others with better scores form peer-review.

One of the drugs being developed based on his work is prasinezumab, which failed to show benefit over placebo in a trial of 316 Parkinson’s patients – but resulting in a host of adverse effects, though none serious. The drug was based on an idea by Masliah and another scientist (whose papers were also seemingly doctored) that a vaccine-like approach could cause the body to create antibodies against harmful precursors in both Parkinson’s and Alzheimer’s.

Questions began to be raised about his research two years ago. These were assessed by a team of forensic analysts and a neuroscientist, who concluded, “In our opinion, this pattern of anomalous data raises a credible concern for research misconduct and calls into question a remarkably large body of scientific work.” They acknowledge that accidental duplication is a possibility, and that images can acquire artefacts resembling improper manipulation during the publication process.

Columbia University neurobiologist Mu Yang used specialised software to detect similarities and alterations in images. She had previously worked with the team investigating manipulation in Alzheimer’s and stroke data. In her analysis, duplicated sections in certain Western blots that had been “seamlessly blended” quickly floated into view, she said. “It tells me someone put a lot of thought and effort into the image … and usually indicates something is very wrong.”

A team of 11 neuroscientists was less charitable when they viewed the images. Samuel Gandy, a prominent neurologist at the Mount Sinai Alzheimer’s Disease Research Center said that he was “floored” by what he saw, noting that even a “bus driver” could see that two images of a mitochondrion published two years apart were identical. “Hundreds of images,” he said in a video interview. “There had to have been ongoing manipulation for years.”

In response to this latest dossier, the NIH issued a statement stating that there was a finding of “research misconduct” for Masliah over reuse of figures in two papers, further stating that Masliah no longer serves as NIA’s neuroscience division director. The NIH stated that it had started its own investigation in 2023.

Source: Science

Categories : Neurodegenerative DiseasesTags :

Two Treatments for Progressive Multiple Sclerosis Fail to Show Benefit

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This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis. Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

In people with primary progressive multiple sclerosis (MS), a new study has found no difference in the amount of time before disability worsened between people taking certain medications and those not receiving treatment. The study is published in Neurology®, the medical journal of the American Academy of Neurology.

With MS, the body’s immune system attacks the myelin sheaths of nerves. People with primary progressive MS experience a steady decline in symptoms. About 10 to 15% of people with the disease have this type of MS.

The study looked at rituximab and ocrelizumab, anti-CD20 infusion therapies that target a protein called CD20 found on some white blood cells called B-cells. Removing these cells from the bloodstream is believed to reduce inflammation and damage that can occur to the myelin.

Ocrelizumab is approved by the US Food and Drug Administration (FDA) for primary progressive MS and for people with relapses, but rituximab is not. Rituximab is FDA approved for other diseases like rheumatoid arthritis and prescribed off label for MS in the US.

“MS is a disabling disease, so treatments that slow the progression to worse disability are sorely needed,” said study author Laure Michel, MD, PhD, of Rennes University in France. “Anti-CD20 therapies are widely prescribed, in part because there are few alternate treatments. However, our study suggests they may not slow disability from worsening for people with primary progressive MS.”

The study involved 1184 people with primary progressive MS who had an average age of 56. They did not take MS medications in the two years prior to the study. For the study, 295 people were treated with rituximab, 131 were treated with ocrelizumab and 728 were untreated.

They were followed for an average of four years. Participants’ level of disability was measured on a scale with scores ranging from zero, meaning no symptoms, to 10 points, meaning death due to MS. At the start of the study, all participants had a score of 6.5 or less. Researchers then measured how long it took for people to advance to their first confirmed disability progression.

For those whose score was less than 5.5 at the start of the study, advancing one point on the scale was considered progressing in disability. If their score was 5.5 or more, advancing 0.5 points on the scale was disability progression.

After adjusting for possible differences between the treated and untreated groups, researchers found there was no difference in the time it took to progress to the next level of disability between those taking a medication and those taking no medication. “

Medications for MS can be expensive and come with risks of side effects,” said Michel. “Our results indicate that there should be a constant evaluation of MS therapies to determine if the benefits outweigh the risks for people with primary progressive MS.”

A limitation of the study was that it was retrospective and did not follow people in real time. Also, among those taking medications, most were taking rituximab with fewer people taking ocrelizumab. More research is needed in larger groups of people to confirm the findings.

Source: American Academy of Neurology

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Why do Some Parkinson’s Disease Treatments Affect Decision Making?

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Parkinson’s disease, a debilitating nervous system disorder, is treated with medications that sometimes cause impaired decision-making and poor impulse control. Now, researchers from Fujita Health University in Japan have identified a structure in the brain called the external globus pallidus which may be responsible for this side effect, paving the way for new treatments.

Parkinson’s disease (PD), also known simply as Parkinson’s, is a disorder of the nervous system that affects millions of people worldwide. The nerve cell damage associated with Parkinson’s can cause tremors, slowed movements, problems with balance, and many other symptoms which worsen gradually over time. Although there is no cure, there are medications available that can treat PD symptoms. Some of these medications, however, have previously unexplained side effects – including impaired decision-making that leads to potentially harmful behaviours such as pathological gambling, binge eating and compulsive shopping.

Now, in a study published in the International Journal of Molecular Sciences, researchers at Fujita Health University in Japan, led by Assistant Professor Hisayoshi Kubota from the Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, have investigated the mechanism by which a drug called pramipexole or PPX impairs the decision-making process in mice with Parkinson’s disease. The research was co-authored by Professor Taku Nagai from the Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), and Professor Hirohisa Watanabe from the Department of Neurology, School of Medicine, both at Fujita Health University.

To take a closer look at the findings of this study, we first need to understand how PPX works to alleviate PD symptoms. PD mainly results from a loss of nerve cells or neurons that produce a compound called dopamine. Some neurons are dependent on dopamine for their regular functioning – they have structures called ‘dopamine receptors’ which can be thought of as locks which can then be activated using dopamine as the ‘key’. Drugs like PPX can imitate the function of dopamine and bind to these receptors instead, especially in patients with PD who lack dopamine-producing neurons.

To study the effects of PPX on PD, the researchers injected the brains of mice with a toxin called 6-hydroxydopamine (or 6-OHDA). 6-OHDA damages neurons in a very similar manner to that observed in the brains of patients with PD. The mice were treated with PPX and then subjected to a touchscreen-based ‘gambling task’ to test their decision-making skills. Interestingly, these mice picked the high-risk/high-reward option much more often – they opted for a disadvantageous outcome where they received a large reward (of strawberry milkshake), which also comes with an increased risk of a large punishment by exposure to flashing lights.

But which part of the brain is responsible for this behaviour? Investigating the brains of mice treated with PPX revealed that a region deep inside the brain called the external globus pallidus (GPe) was hyperactivated, or showed a much higher level of neuron activity. The researchers then chemically inhibited the neurons in the GPe, which actually reduced disadvantageous risk-taking activity in the mice. This proved that hyperactivation of the GPe was indeed responsible for poor decision-making in the mice treated with PPX.

This study has huge implications for treating patients with Parkinson’s disease. “Our findings could lead to the development of new medications or interventions that specifically target the external globus pallidus,” explains Dr. Kubota. “This would help to prevent or reduce decision-making impairments in Parkinson’s disease patients.“

Besides helping medical professionals develop better treatments for Parkinson’s disease, these findings can also help improve awareness among affected patients, their families, as well as the general public. Dr. Kubota, explains that “Investigating how Parkinson’s disease medications affect decision-making will help the public to better understand the complexity of the disease and its treatment.” He also says “This will benefit patients, their families and carers, and motivate them to consider early care and preventive strategies.”

These findings shed new light on the complex processes in the brain that aid our everyday decision-making skills, and promise to improve quality of life for patients affected by Parkinson’s disease. Maybe we can take away some important lessons from this study as well, and think twice before we indulge in poor decision-making in our daily lives!

Categories : Neurodegenerative DiseasesTags :

SGLT-2 Inhibitors may Lower Risk of Dementia and Parkinson’s Disease

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A class of drugs for diabetes may be associated with a lower risk of dementia and Parkinson’s disease, according to a study published in Neurology®, the medical journal of the American Academy of Neurology. The study looked at sodium-glucose cotransporter-2 (SGLT2) inhibitors, which are also known as gliflozins. They lower blood sugar by causing the kidneys to remove sugar from the body through urine.

“We know that these neurodegenerative diseases like dementia and Parkinson’s disease are common and the number of cases is growing as the population ages, and people with diabetes are at increased risk of cognitive impairment, so it’s encouraging to see that this class of drugs may provide some protection against dementia and Parkinson’s disease,” said study author Minyoung Lee, MD, PhD, of Yonsei University College of Medicine in Seoul, South Korea.

The retrospective study looked at people with type 2 diabetes who started diabetes medication from 2014 to 2019 in South Korea. People taking SGLT2 inhibitors were matched with people taking other oral diabetes drugs, so the two groups had people with similar ages, other health conditions and complications from diabetes.

Then researchers followed the participants to see whether they developed dementia or Parkinson’s disease. Those taking the SGLT2 inhibitors were followed for an average of two years and those taking the other drugs were followed for an average of four years.

Among the 358 862 participants with an average age of 58, a total of 6837 people developed dementia or Parkinson’s disease during the study. For Alzheimer’s disease, the incidence rate for people taking SGLT2 inhibitors was 39.7 cases per 10 000 person-years, compared to 63.7 cases for those taking other diabetes drugs. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

For vascular dementia, which is dementia caused by vascular disease, the incidence rate for people taking the SGLT2 drugs was 10.6 cases per 10 000, compared to 18.7 for those taking the other drugs. For Parkinson’s disease, the incidence rate for those taking the SGLT2 drugs was 9.3 cases per 10 000, compared to 13.7 for those taking the other drugs.

After researchers adjusted for other factors that could affect the risk of dementia or Parkinson’s disease, such as complications from diabetes and medications, they found that SGLT2 inhibitor use was associated with a 20% reduced risk of Alzheimer’s disease and a 20% reduced risk of Parkinson’s disease. Those taking the drugs had a 30% reduced risk of developing vascular dementia.

“The results are generally consistent even after adjusting for factors like blood pressure, glucose, cholesterol and kidney function,” Lee said. “More research is needed to validate the long-term validity of these findings.” Lee said that since participants were followed for less than five years at the most, it’s possible that some participants would later develop dementia or Parkinson’s disease.

Source: American Academy of Neurology

Categories : Neurodegenerative DiseasesTags :

Treatment with Dopamine Alleviates Symptoms in Alzheimer’s Disease

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Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH

A new way to combat Alzheimer’s disease has been discovered by Takaomi Saido and his team at the RIKEN Center for Brain Science (CBS) in Japan. Using mouse models, the researchers found that treatment with dopamine could alleviate physical symptoms in the brain as well as improve memory. Published in Science Signaling, the study examines dopamine’s role in promoting the production of neprilysin, an enzyme that can break down the harmful plaques in the brain that are the hallmark of Alzheimer’s disease. If demonstrated in human clinical trials, it could lead to a fundamentally new way to treat the disease.

The formation of hardened plaques around neurons is one of the earliest signs of Alzheimer’s disease, often beginning decades before behavioural symptoms such as memory loss are detected. These plaques are formed from pieces of the peptide beta-amyloid that accumulate over time. In the new study, Saido’s team at RIKEN CBS focuses on the enzyme neprilysin because previous experiments showed that genetic manipulation that produces excess neprilysin in the brain (a process called upregulation) resulted in fewer beta-amyloid plaques and improved memory in mice.

Neprilysin by itself cannot be a medication as it cannot enter the brain from the blood stream, so the researchers screened molecules to determine which ones can naturally upregulate neprilysin in the correct parts of the brain. The team’s previous research led them to narrow down the search to hormones produced by the hypothalamus, and they discovered that applying dopamine to brain cells cultured in a dish yielded increased levels of neprilysin and reduced levels of free-floating beta-amyloid.

Now the serious experiments began. Using a DREADD system, they inserted tiny designer receptors into the dopamine producing neurons of the mouse ventral tegmental area. By adding a matching designer drug to the mice’s food, the researchers were able to continuously activate those neurons, and only those neurons, in the mouse brains. As in the dish, activation led to increased neprilysin and decreased levels of free-floating beta-amyloid, but only in the front part of the mouse brain. But could the treatment remove plaques? Yes. The researchers repeated the experiment using a special mouse model of Alzheimer’s disease in which the mice develop beta-amyloid plaques. Eight weeks of chronic treatment resulted in significantly fewer plaques in the prefrontal cortex of these mice.

The DREADD system is an incredible system for precise manipulation of specific neurons. But it is not very useful for human clinical settings. The final experiments tested the effects of L-DOPA treatment. L-DOPA is a dopamine precursor molecule often used to treat Parkinson’s disease because it can enter the brain from the blood, where it is then converted into dopamine. Treating the model mice with L-DOPA led to increased neprilysin and decreased beta-amyloid plaques in both frontal and posterior parts of the brain. Model mice treated with L-DOPA for three months also performed better on memory tests than untreated model mice.

Tests showed that neprilysin levels naturally decreased with age in normal mice, particularly in the frontal part of the brain, perhaps making it a good biomarker for preclinical or at-risk Alzheimer’s disease diagnoses. How dopamine causes neprilysin levels to increase remains unknown, and is the next research topic for Saido’s group.

“We have shown that L-DOPA treatment can help reduce harmful beta-amyloid plaques and improve memory function in a mouse model of Alzheimer’s disease,” explains Watamura Naoto, first author of the study. “But L-DOPA treatment is known to have serious side effects in patients with Parkinson’s disease. Therefore, our next step is to investigate how dopamine regulates neprilysin in the brain, which should yield a new preventive approach that can be initiated at the preclinical stage of Alzheimer’s disease.”

Source: RIKEN

Categories : Neurodegenerative DiseasesTags :

New Paper Suggests that MS Protects Against Alzheimer’s Disease

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Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH

People with multiple sclerosis (MS) are far less likely than those without the condition to have the molecular hallmarks of Alzheimer’s disease, according to a paper published in the Annals of Neurology.

The study from Washington University School of Medicine in St. Louis, suggests a new direction for researching Alzheimer’s treatments, said Matthew Brier, MD PhD, an assistant professor of neurology and radiology and the study’s first author.

“Our findings imply that some component of the biology of multiple sclerosis, or the genetics of MS patients, is protective against Alzheimer’s disease,” Brier said. “If we could identify what aspect is protective and apply it in a controlled way, that could inform therapeutic strategies for Alzheimer’s disease.”

A collaboration between WashU Medicine experts in Alzheimer’s and MS, the study was prompted by a suspicion Brier’s mentor and collaborator Anne Cross, MD, had developed over decades of treating patients with MS, an immune-mediated disease that attacks the central nervous system. Although her patients were living long enough to be at risk of Alzheimer’s or had a family history of the neurodegenerative disease, they weren’t developing the disease.

“I noticed that I couldn’t find a single MS patient of mine who had typical Alzheimer’s disease,” said Cross, the Manny and Rosalyn Rosenthal and Dr. John Trotter MS Center Chair in Neuroimmunology. “If they had cognitive problems, I would send them to the memory and aging specialists here at the School of Medicine for an Alzheimer’s assessment, and those doctors would always come back and tell me, ‘No, this is not due to Alzheimer’s disease.’”

Cognitive impairment caused by MS can be confused with symptoms of Alzheimer’s disease; Alzheimer’s can be confirmed with blood and other biological tests.

To confirm Cross’ observation, the research team used a new, FDA-approved blood test that was developed by Washington University researchers. Known as PrecivityAD2, the blood test is highly effective at predicting the presence of amyloid plaques in the brain. Such plaques are an indicator of Alzheimer’s disease and previously only could be verified with brain scans or spinal taps.

Brier, Cross and their colleagues recruited 100 patients with MS to take the blood test, 11 of whom also underwent PET scans at the School of Medicine’s Mallinckrodt Institute of Radiology. Their results were compared with the results from a control group of 300 individuals who did not have MS but were similar to those with MS in age, genetic risk for Alzheimer, and cognitive decline.

“We found that 50% fewer MS patients had amyloid pathology compared to their matched peers based on this blood test,” Brier said. This finding supported Cross’ observation that Alzheimer’s appeared to be less likely to develop among those with MS. It is not clear how amyloid accumulation is linked to the cognitive impairment typical of Alzheimer’s, but the accumulation of plaques is generally understood to be the first event in the biological cascade that leads to cognitive decline.

The researchers also found that the more typical the patient’s MS history was, in terms of age of onset, severity and overall disease progression, the less likely they were to have amyloid plaque accumulation in that patient’s brain compared with those with atypical presentations of MS. This suggests there is something about the nature of MS itself that is protective against Alzheimer’s disease, which Brier and Cross are planning to investigate.

MS patients generally have multiple flare-ups of the illness over the course of their lifetimes. During these flare-ups, the immune system attacks the central nervous system, including within the brain. It’s possible that this immune activity also reduces amyloid plaques, the researchers said.

“Perhaps when the Alzheimer’s disease amyloid pathology was developing, the patients with MS had some degree of inflammation in their brains that was spurred by their immune responses,” Brier said. Referring to work by co-author David M. Holtzman, MD, Brier noted that activated microglia, which are part of the brain’s immune response in MS, have been shown to clear amyloid from the brain in animal models.

Brier and Cross have begun the next steps of this research, both to tease out the possible human genetics involved, as well as to test amyloid plaque development in animal models representing MS.

Source: Washington University School of Medicine

Categories : Genetics Neurodegenerative DiseasesTags :

A New Genetic Culprit in Huntington’s Disease

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Researchers in Berlin and Düsseldorf have implicated a new gene in the progression of Huntington’s disease in a brain organoid model. The gene may contribute to brain abnormalities much earlier than previously thought. The study is out now in Nature Communications.

The researchers are the first to implicate the gene CHCHD2 in Huntington’s disease (HD) – an incurable genetic neurodegenerative disorder – and identified the gene as a potentially new therapeutic target. In a brain organoid model of the disease, the researchers found that mutations in the Huntington gene HTT also affect CHCHD2, which is involved in maintaining the normal function of mitochondria.

Six different labs at the Max Delbrück Center participated in the study, led by Dr Jakob Metzger of the “Quantitative Stem Cell Biology” lab at the and the “Stem Cell Metabolism” lab of Professor Alessandro Prigione at Heinrich Heine University Düsseldorf (HHU). Each lab contributed their unique expertise on Huntington’s disease, brain organoids, stem cell research and genome editing. “We were surprised to find that Huntington’s disease can impair early brain development through defects associated with mitochondrial dysfunction,” says Dr Pawel Lisowski, co-lead author in the Metzger lab at the Max Delbrück Center.

Moreover, “the organoid model suggests that HTT mutations damage brain development even before clinical symptoms appear, highlighting the importance of detecting the late-onset neurodegenerative disease early,” Selene Lickfett, co-lead author and a doctoral student in the Faculty of Mathematics and Natural Science in the lab of Prigione at HHU adds.

The unusual repetition of three letters

Huntington’s disease is caused when the nucleotides Cytosine, Adenine and Guanine are repeated an excessive number of times in the in the Huntington gene HTT. People with 35 or less repeats are generally not at risk of developing the disease, while carrying 36 or more repeats has been associated with disease. The greater the number of repeats, the earlier the disease symptoms are likely to appear, explains Metzger, a senior author of the study. The mutations cause nerve cells in the brain to progressively die. Those affected, steadily lose muscle control and develop psychiatric symptoms such as impulsiveness, delusions and hallucinations. Huntington’s disease affects approximately five to 10 in every 100 000 people worldwide. Existing therapies only treat the symptoms of the disease, they don’t slow its progression or cure it.

The challenge of HTT gene editing

To study how mutations in the HTT gene affect early brain development, Lisowski, first used variants of the Cas9 gene editing technology and manipulation of DNA repair pathways to modify healthy induced pluripotent stem cells such that they carry a large number of CAG repeats. This was technically challenging because gene editing tools are not efficient in gene regions that contain sequence repeats, such as the CAG repeats in HTT, says Lisowski.

The genetically modified stem cells were then grown into brain organoids – three-dimensional structures a few millimetres in size that resemble early-stage human brains. When the researchers analysed gene expression profiles of the organoids at different stages of development, they noticed that the CHCHD2 gene was consistently under expressed, which reduced metabolism of neuronal cells. CHCHD2 is involved in ensuring the health of mitochondria – the energy producing structures in cells. CHCHD2 has been implicated in Parkinson’s disease, but never before in Huntington’s.

They also found that when they restored the function of the CHCHD2 gene, they could reverse the effect on neuronal cells. “That was surprising,” says Selene Lickfett. “It suggests in principle that this gene could be a target for future therapies.”

Moreover, defects in neural progenitor cells and brain organoids occurred before potentially toxic aggregates of mutated Huntingtin protein had developed, adds Metzger, indicating that disease pathology in the brain may begin long before it is clinically evident.

“The prevalent view is that the disease progresses as a degeneration of mature neurons,” says Prigione. “But if changes in the brain already develop early in life, then therapeutic strategies may have to focus on much earlier time-points.”

Wide reaching implications

“Our genome editing strategies, in particular the removal of the CAG repeat region in the Huntington gene, showed great promise in reversing some of observed developmental defects. This suggests a potential gene therapy approach,” says Prigione. Another potential approach could be therapies to increase CHCHD2 gene expression, he adds.

The findings may also have broader applications for other neurodegenerative diseases, Prigione adds. “Early treatments that reverse the mitochondrial phenotypes shown here could be a promising avenue for counteracting age-related diseases like Huntington’s disease.”

Source: Max Delbrück Center for Molecular Medicine in the Helmholtz Association