Category: Neurodegenerative Diseases

Categories : Mental Health Neurodegenerative DiseasesTags :

Parkinson’s Drug Effective in Treating Persistent Depression

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Photo by Andrew Neel on Unsplash

In the largest clinical trial to date, pramipexole was found to be substantially more effective than a placebo at reducing the symptoms of treatment resistant depression (TRD) over the course of nearly a year, when added to ongoing antidepressant medication.

The trial, supported by National Institute for Health and Care Research (NIHR) and published in The Lancet Psychiatry, included 150 patients with treatment resistant depression, with equal numbers receiving 48 weeks of pramipexole or a placebo, alongside ongoing antidepressant medication.

Overall, the group taking pramipexole experienced a significant and substantial reduction in symptoms by week twelve of treatment, with the benefits persisting over the course of a year. However, there were also significant side effects, such as nausea, sleep disturbance and dizziness, with around one in five people on pramipexole dropping out of the trial as a result.

Professor Michael Browning, from the Department of Psychiatry, University of Oxford, and workstream lead in Mood Disorders for the NIHR Mental Health-Translational Research Collaboration (MH-TRC) Mission, who led the trial, said: ‘Effectively treating people who have not responded to first-line interventions for depression is a pressing clinical problem and there has long been an urgent need to find new treatments.

‘These findings on pramipexole are a significant breakthrough for patients for whom antidepressants and other treatments and therapies have not worked.

‘Pramipexole is a medicine licensed for Parkinson’s disease and works by boosting the brain chemical dopamine. This differs from the majority of other antidepressant medications which act on brain serotonin and may explain why pramipexole was so helpful in this study.

‘We now need more research focusing on reducing the side effects of pramipexole, evaluating its cost-effectiveness, and comparing it with other add-on treatments.’

Previous research into using the drug for depression had shown promise, but there had been limited data on its long-term outcomes and side effects until now.

Current guidelines for people with treatment resistant depression recommend adding new treatments, such as lithium or antipsychotics, to ongoing antidepressant treatment, but these have limited effectiveness and do not work for everyone.

Phil Harvey, 72, from Oxfordshire, was diagnosed with depression 20 years ago and tried different tablets and counselling but nothing worked. Eventually he had to take a year off work before retiring. He started on the trial in 2022.

He said: ‘Within a few weeks I felt the effects, it was amazing. I kept a diary which they gave us on how my mood was, motivation and how it improved. It was dragging me out of this dark black hole that I’ve been in for years.’

Participants were recruited from across the country, including as part of the NIHR-funded MH-TRC Mission mood disorder clinics, which are hosted at Oxford but located across the country. The clinics efficiently, and largely remotely, assess patients with difficult to treat mood disorders and offer them enrolment in research studies. The network can also support primary care services by providing assessment and treatment advice for patients who have not responded to initial treatment.

Source: University of Oxford

Categories : Neurodegenerative Diseases New Compounds and TreatmentsTags :

Weekly Gel-based Injection for Parkinson’s Could Be a Game Changer

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A new weekly injectable drug could transform the lives of more than eight million people living with Parkinson’s disease, potentially replacing the need for multiple daily tablets.

UniSA PhD candidate Deepa Nakmode and Professor Sanjay Garg in the lab. Credit: UniSA

Scientists from the University of South Australia (UniSA) have developed a long-acting injectable formulation that delivers a steady dose of levodopa and carbidopa – two key medications for Parkinson’s – over an entire week.

Their findings have been reported in the journal Drug Delivery and Translational Research.

The biodegradable formulation is delivered in a subcutaneous or intramuscular injection, where it gradually releases the medication over seven days.

Parkinson’s disease is the second most common neurological disorder, affecting more than 8.5 million people worldwide. Currently there is no cure and the symptoms – tremors, rigidity and slow movement – are managed with oral medications that must be taken several times a day.

The frequent dosing is a burden, especially for elderly patients or those with swallowing difficulties, leading to inconsistent medication levels, more side effects, and reduced effectiveness.

Lead researcher Professor Sanjay Garg, from UniSA’s Centre for Pharmaceutical Innovation, says the newly developed injectable could significantly improve treatment outcomes and patient adherence.

“Our goal was to create a formulation that simplifies treatment, improves patient compliance, and maintains consistent therapeutic levels of medication. This weekly injection could be a game-changer for Parkinson’s care,” Prof Garg says.

“Levodopa is the gold-standard therapy for Parkinson’s, but its short life span means it must be taken several times a day.”

UniSA PhD student Deepa Nakmode says the in-situ implant is designed to release both levodopa and carbidopa steadily over one week, maintaining consistent plasma levels and reducing the risks associated with fluctuating drug concentrations.

“After years of focused research, it’s incredibly rewarding to see our innovation in long-acting injectables for Parkinson’s disease reach this stage. Our invention has now been filed for an Australian patent,” Nakmode says.

The injectable gel combines an FDA-approved biodegradable polymer PLGA with Eudragit L-100, a pH-sensitive polymer, to achieve a controlled and sustained drug release.

Extensive lab tests confirmed the system’s effectiveness and safety:

  • More than 90% of the levodopa dose and more than 81% of the carbidopa dose was released over seven days.
  • The implant degraded by over 80% within a week and showed no significant toxicity in cell viability tests.
  • The formulation can be easily administered through a fine 22-gauge needle, minimising discomfort and eliminating the need for surgical implant.

“The implications of this research are profound,” Prof Garg says. “By reducing the frequency of dosing from multiple times a day to a weekly injection is a major step forward in Parkinson’s therapy. We’re not just improving how the drug is delivered; we’re improving patients’ lives.”

Prof Garg says the technology could also be adapted for other chronic conditions such as cancer, diabetes, neurodegenerative disorders, pain management, and chronic infections that require long-term drug delivery.in

The system can be tuned to release drugs over a period ranging from a few days to several weeks depending on therapeutic needs.

UniSA scientists hope to start clinical trials in the near future and are exploring commercialisation opportunities.

Source: University of South Australia

Categories : Neurodegenerative DiseasesTags :

A Cough Medicine Shows Potential to Slow Parkinson’s-related Dementia

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Photo by cottonbro studio

Dementia poses a major health challenge with no safe, affordable treatments to slow its progression. Researchers at Lawson Research Institute (Lawson), the research arm of St. Joseph’s Health Care London, are investigating whether Ambroxol – a cough medicine used safely for decades in Europe – can slow dementia in people with Parkinson’s disease.  

Published in JAMA Neurology, this 12-month clinical trial involving 55 participants with Parkinson’s disease dementia (PDD) monitored memory, psychiatric symptoms and GFAP, a blood marker linked to brain damage. 

Parkinson’s disease dementia causes memory loss, confusion, hallucinations and mood changes. About half of those diagnosed with Parkinson’s develop dementia within 10 years, profoundly affecting patients, families and the health care system. 

Led by Cognitive Neurologist Dr Stephen Pasternak, the study gave one group daily Ambroxol while the other group received a placebo.  

“Our goal was to change the course of Parkinson’s dementia,” says Pasternak. “This early trial offers hope and provides a strong foundation for larger studies.” 

Key findings from the clinical trial include: 

  • Ambroxol was safe, well-tolerated and reached therapeutic levels in the brain. 
  • Psychiatric symptoms worsened in the placebo group but remained stable in those taking Ambroxol. 
  • Participants with high-risk GBA1 gene variants showed improved cognitive performance on Ambroxol. 
  • A marker of brain cell damage (GFAP) increased in the placebo group but stayed stable with Ambroxol, suggesting potential brain protection.

Although Ambroxol is approved in Europe for treating respiratory conditions and has a long-standing safety record – including use at high doses and during pregnancy – it is not approved for any use in Canada or the U.S. 

“Current therapies for Parkinson’s disease and dementia address symptoms but do not stop the underlying disease,” explains Pasternak. “These findings suggest Ambroxol may protect brain function, especially in those genetically at risk. It offers a promising new treatment avenue where few currently exist.” 

An old drug with new possibilities  

Ambroxol supports a key enzyme called glucocerebrosidase (GCase), which is produced by the GBA1 gene. In people with Parkinson’s disease, GCase levels are often low. When this enzyme doesn’t work properly, waste builds up in brain cells, leading to damage. 

Pasternak learned about Ambroxol during a fellowship at The Hospital for Sick Children (SickKids) in Toronto, where it was identified as a treatment for Gaucher disease – a rare genetic disorder in children caused by a deficiency of GCase. He is now applying that research to explore whether boosting GCase with Ambroxol could help protect the brain in Parkinson’s related diseases. 

“This research is vital because Parkinson’s dementia profoundly affects patients and families,” says Pasternak. “If a drug like Ambroxol can help, it could offer real hope and improve lives.” 

Funded by the Weston Family Foundation, this study is an important step toward developing new treatments for Parkinson’s disease and other cognitive disorders, including dementia with Lewy bodies. Pasternak and his team plan to start a follow-up clinical trial focused specifically on cognition later this year. 

Source: St. Joseph’s Health Care London

Categories : Neurodegenerative Diseases PaediatricsTags :

Why Do Newborns Have Elevated Levels of an Alzheimer’s Biomarker?

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What do the brains of newborns and patients with Alzheimer’s disease have in common? Researchers from the University of Gothenburg, led by first author Fernando Gonzalez-Ortiz and senior author Professor Kaj Blennow, recently reported that both newborns and Alzheimer’s patients have elevated blood levels of a protein called phosphorylated tau, specifically a form called p-tau217.

While this protein has been largely used as a diagnostic test for Alzheimer’s disease, with an increase in p-tau217 blood levels proposed to be driven by another process, namely aggregation of b-amyloid protein into amyloid plaques. Newborns (for natural reasons) do not have this type of pathological change, so interestingly, in newborns increased plasma p-tau217 seems to reflect a completely different – and entirely healthy – mechanism.

In a large international study that involved Sweden, Spain and Australia, researchers analyzed blood samples from over 400 individuals, including healthy newborns, premature infants, young adults, elderly adults, and people diagnosed with Alzheimer’s disease. They found that newborn babies had the highest levels of p-tau217 – even higher than those found in people with Alzheimer’s. These levels were particularly elevated in premature babies and started to decrease over the first few months of life, eventually settling to adult levels.

First time in the blood of newborns

Previous research, largely based on animal models, had hinted at the role of phosphorylated tau in early brain development. This is the first time scientists have directly measured p-tau217 concentrations in the blood of human newborns, opening the door to a much clearer understanding of its developmental role.

But here’s where it gets fascinating, while in Alzheimer’s disease p-tau217 is associated with tau aggregation into harmful clumps called tangles, believed to cause the breakdown of brain cells and subsequent cognitive decline. In contrast, in newborns this surge in tau appears to support healthy brain development, helping neurons grow and to form new connections with other neurons, thereby shaping the structure of the young brain.

The study also revealed that in both healthy and premature babies, p-tau217 levels were closely linked to how early they were born. The earlier the birth, the higher the levels of this protein, suggesting a role in supporting rapid brain growth under challenging developmental conditions.

Potential roadmap for new treatments 

What’s perhaps most compelling about these findings, published in the journal Brain Communications, is the hint that our brains may once have had built-in protection against the damaging effects of tau, so that newborns can tolerate, and even benefit from, high levels of phosphorylated tau without triggering the kinds of damage seen in Alzheimer’s.

“We believe that understanding how this natural protection works – and why we lose it as we age – could offer a roadmap for new treatments. If we can learn how the newborn brain keeps tau in check, we might one day mimic those processes to slow or stop Alzheimer’s in its tracks”, says Fernando Gonzalez-Ortiz.

So while an increase of p-tau217 is a danger signal in older brains, in newborns it might be a vital part of building one. The same molecule, two dramatically different roles – one building the brain, the other marking its decline.

Plasma p-tau217 has recently received FDA approval for use in diagnosing Alzheimer’s disease, making it an increasingly important tool in clinical settings. The authors emphasise

Source: the need to also understand the mechanism for the increase in p-tau217, especially for interpreting it as an outcome in clinical and epidemiological research and in drug development. This study indicate that amyloid plaques may not be the main driver of increases in p-tau217.

Source: University of Gothenburg

Categories : Neurodegenerative Diseases New Compounds and TreatmentsTags :

Royalty-based Method Offers New Model for ALS Drug Development

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A team of researchers from the MIT Sloan School of Management, the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH), Questrom School of Business at Boston University, and QLS Advisors have introduced a new approach to funding clinical trials for amyotrophic lateral sclerosis (ALS) therapies. The study, “Financing Drug Development via Adaptive Platform Trials,” published today in PLOS One, outlines a financing model that merges the efficiencies of adaptive platform trials — lower costs and shorter durations — with an innovative, royalty-based investment structure designed to accelerate therapeutic development for ALS and other serious diseases.

ALS — also often called Lou Gehrig’s disease — is a progressive, neurodegenerative disease with no cure. Despite its devastating impact, the pace of new therapy development has remained sluggish—largely due to the high cost, duration, and risks associated with traditional clinical trials. This bottleneck has often discouraged conventional investors, leaving promising research to languish.

To tackle this challenge, the authors propose an investment fund that finances half the cost of an adaptive platform trial in exchange for future royalties from successful drugs that emerge from the trial. Adaptive platform trials allow multiple drug candidates to be tested simultaneously under a single master protocol, and results are interpreted on a real-time basis to determine efficacy or futility. Drawing on data from the HEALEY ALS Platform Trial administered by the Healey & AMG Center for ALS at MGH, and realistic assumptions, their simulated fund generated an expected return of 28%, with a 22% probability of total loss, which may be attractive to more risk-tolerant and impact-driven investors such as hedge funds, sovereign wealth funds, family offices, and philanthropists. Their findings suggest that generating returns more palatable for mainstream investors could be achieved by funding multiple platform trials simultaneously and by employing financial tools such as securitization — a method that bundles future income from assets like loans or royalties into investment products.

“ALS clinical trials face significant hurdles — from high costs and long timelines to limited funding pools,” said Merit E. Cudkowicz, MD, MSC, Executive Director at Mass General Brigham Neuroscience Institute and Director of the Healey & AMG Center for ALS. “Our platform trial model has already shown that we can test more therapies more efficiently. What’s still missing is sustainable financing. This novel approach could be a game-changer, enabling us to launch trials faster, include more promising therapies, and bring us closer to our shared goal: delivering effective treatments to people with ALS as quickly as possible.”

While their study focused on ALS, the authors believe such a funding model could be applied to other disease areas as well, especially those with well-defined endpoints, where treatment success can be measured clearly and reliably.

Source: Mass General Brigham

Categories : Neurodegenerative DiseasesTags :

Mitochondrial Failure Contributes to Neuron Death in Multiple Sclerosis

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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

Multiple sclerosis (MS) affects some 2.3 million people worldwide, with 80% experiencing inflammation in the cerebellum, a brain region crucial for movement and balance. This inflammation can lead to tremors, poor coordination, and motor control issues, which often worsen over time due to the loss of healthy brain tissue.

Researchers at the University of California, Riverside, have made a significant discovery about the underlying mechanisms of cerebellar degeneration in MS. Their study, published in PNAS, suggests that mitochondrial dysfunction may play a key role in the progressive loss of Purkinje cells and worsening motor impairments.

Purkinje cells are essential for coordinating smooth movements and balance. In MS, these cells can be damaged, leading to problems with coordination and movement, known as ataxia. The study found that Purkinje cells in MS patients had fewer branches, lost myelin, and experienced mitochondrial problems, resulting in a failing energy supply.

“Our study, conducted by my graduate student Kelley Atkinson, proposes that inflammation and demyelination in the cerebellum disrupt mitochondrial function, contributing to nerve damage and Purkinje cell loss,” said Seema Tiwari-Woodruff, a professor of biomedical sciences in the UC Riverside School of Medicine, who led the research team. “We observed a significant loss of the mitochondrial protein COXIV in demyelinated Purkinje cells, suggesting that mitochondrial impairment contributes directly to cell death and cerebellar damage.”

The research team used a mouse model of MS to investigate mitochondrial alterations during disease progression. They found that the mice lost Purkinje cells over time, similar to people with MS. The loss of energy seemed to be a key part of MS, with cells only dying later.

“Our research looked at brain tissue from MS patients and found major issues in these neurons: they had fewer branches, were losing myelin, and had mitochondrial problems – meaning their energy supply was failing,” Tiwari-Woodruff said. “Because Purkinje cells play such a central role in movement, their loss can cause serious mobility issues. Understanding why they’re damaged in MS could help us find better treatments to protect movement and balance in people with the disease.”

The study suggests that targeting mitochondrial health may be a promising strategy to slow or prevent neurological decline and improve quality of life for people living with MS.

The researchers plan to further investigate whether mitochondrial impairment affects other brain cells, such as oligodendrocytes and astrocytes. This research has the potential to open the door to finding ways to protect the brain early on, such as boosting energy in brain cells or aiding repair of the myelin sheaths.

Source: University of California, Riverside

Categories : Neurodegenerative Diseases VaccinesTags :

RSV Vaccine Reduces the Risk of Dementia, New Research Shows

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A new study by the University of Oxford, published in the journal npj Vaccines, shows that a vaccine against respiratory syncytial virus (RSV) is associated with a 29% reduction in dementia risk in the following 18 months. The findings suggest a novel explanation for how vaccines produce this effect.

Recent studies have shown convincingly that vaccines against shingles (Herpes zoster) reduce the risk of dementia. The shingles vaccine now in widespread use (Shingrix) has more of an effect than the previous one (Zostavax). A key difference between these vaccines is that Shingrix contains an ‘adjuvant’, an ingredient designed to enhance the vaccine’s effect. It is therefore possible that the adjuvant contributes to Shingrix’ greater effect than Zostavax on reducing dementia.

The new study, supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre (OH BRC), supports this possibility. Researchers analysed the health records of over 430 000 people in the USA in the TriNetX network. They found that the Arexvy vaccine – which protects against respiratory syncytial virus (RSV), a common virus that causes cold-like symptoms – was also linked to a significantly lower risk of developing dementia. Arexvy, now offered to adults over 60, contains the same adjuvant as Shingrix. Both vaccines were similarly effective in reducing dementia risk compared to the flu vaccine (which does not contain the adjuvant); in the 18 months following receipt of Arexvy there was a 29% reduction in diagnoses of dementia. These findings held true across a range of additional analyses and were similar in men and women.

It is not clear how the adjuvant, called AS01, might help lower the risk of dementia. However, laboratory studies show that AS01 stimulates cells of the immune system that could help protect the brain from some of the harmful processes underlying dementia. These benefits of the adjuvant in reducing dementia risk could be in addition to the protection that comes from preventing infections like shingles and RSV themselves.

It is not yet known whether these vaccines prevent dementia or, more likely, delay its onset. Either way, the effect is significant, especially given that no other treatments are known that delay or prevent the condition.

The likely beneficial effect on dementia risk is in addition to the vaccines’ proven ability to prevent shingles and RSV, both of which are unpleasant and sometimes serious illnesses.

Lead author, Associate Professor Maxime Taquet, NIHR Academic Clinical Lecturer, Department of Psychiatry, University of Oxford, said: “Our findings show that vaccines against two separate viruses, shingles and RSV, both lead to reductions in dementia. This gives another reason to have the vaccines, in addition to their effectiveness at preventing these serious illnesses.’

Senior author, Professor Paul Harrison, Department of Psychiatry, University of Oxford and Co-Lead for the Molecular Targets theme in OH BRC, said: ‘The findings are striking. We need studies to confirm whether the adjuvant present in some vaccines contributes to the reduced dementia risk, and to understand how it does so.’

Source: Oxford University

Categories : Cancer Neurodegenerative DiseasesTags :

Breast Cancer Treatment Linked to a Reduction in Alzheimer’s Disease Risk

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A Korean population-based cohort study investigated the risk of Alzheimer’s disease (AD) among breast cancer survivors compared to age-matched controls without cancer. The study, published in JAMA Network Open, found that breast cancer survivors had an 8% lower risk of AD than controls, with a significant association in survivors over 65 years old – though the effect did not persist past five years. Radiotherapy was associated with a lower risk of AD among breast cancer survivors – but not other treatments.

Breast cancer survivors may experience long-term health consequences, including cognitive function and risk of dementia. The risk of AD among breast cancer survivors is still unclear and may vary depending on age at diagnosis, treatment received, and time since treatment.

Previous studies reported mixed results on the risk of AD among breast cancer survivors, with some finding no increase in risk and others finding a 35% increased risk for those diagnosed at age 65 or older. These studies have been hampered by a number of methodological issues, including not accounting for risk factors.

Cytotoxic chemotherapy can cause cognitive decline termed ‘chemobrain’. Other chemotherapy drugs such as anthracycline may reduced AD risk by reducing the formation of amyloid deposits. Endocrine therapy may increase the risk of dementia by lowering oestrogen, but studies suggest that the use of tamoxifen and aromatase inhibitors is associated with a lower risk of AD. An increase in dementia is seen in radiotherapy for head and neck cancers.

To investigate the risk of AD among breast cancer survivors, researchers used the Korean National Health Insurance Service (K-NHIS) database, exploring whether there is an association with cancer treatment and various confounding factors.

Among 70 701 breast cancer survivors (mean age, 53.1 years), 1229 cases of AD were detected, with an incidence rate of 2.45 per 1000 person-years. Survivors exhibited a slightly lower risk of AD compared with cancer-free controls, especially among individuals 65 years or older (SHR, 0.92; 95% CI, 0.85-0.99). But landmark analyses found that this lower risk did not persist beyond five years of survival. Radiotherapy was associated with reduced risk of AD among survivors, while chemotherapy and endocrine therapy had no significant impact. Anthracycline use, however, did show a non-significant decrease in risk.

Differences in doses and timing of radiotherapy may influence the effects. The incident exposure to the brain is estimated to be 0.2Gy from a breast cancer radiotherapy dose of 50Gy. A pilot study found that patients with AD who received low-dose whole-brain radiotherapy at 3Gy showed a temporary improvement in cognitive function. This improvement is believed to be due to a neuroprotective effect on microglia. Other studies have noted a transient risk reduction for AD in breast cancer radiotherapy; however, patients receiving radiotherapy usually do so in conjunction with breast-conserving surgery – those opting for this procedure are younger, with fewer comorbidities and smaller tumours.

The study suggests that cancer treatment may have benefits against AD development, but the risk of AD may differ depending on the duration of survival.

The findings indicate that breast cancer treatment may not directly lead to AD, and that managing modifiable risk factors for AD, such as smoking and diabetes, is a feasible option to lower AD risk among breast cancer survivors.

Categories : Genetics Neurodegenerative DiseasesTags :

Iron Plays a Major Role in Down Syndrome-Associated Alzheimer’s Disease

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New USC research indicates how iron-related oxidative damage and cell death may hasten the development of Alzheimer’s disease in people with Down syndrome

Photo by Nathan Anderson on Unsplash

Scientists at the University of Southern Carolina have discovered a key connection between high levels of iron in the brain and increased cell damage in people who have both Down syndrome and Alzheimer’s disease.

In the study, researchers found that the brains of people diagnosed with Down syndrome and Alzheimer’s disease (DSAD) had twice as much iron and more signs of oxidative damage in cell membranes compared to the brains of individuals with Alzheimer’s disease alone or those with neither diagnosis. The results, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, point to a specific cellular death process that is mediated by iron, and the findings may help explain why Alzheimer’s symptoms often appear earlier and more severely in individuals with Down syndrome.

“This is a major clue that helps explain the unique and early changes we see in the brains of people with Down syndrome who develop Alzheimer’s,” said Max Thorwald, lead author of the study and a postdoctoral fellow in the laboratory of University Professor Emeritus Caleb Finch at the USC Leonard Davis School. “We’ve known for a long time that people with Down syndrome are more likely to develop Alzheimer’s disease, but now we’re beginning to understand how increased iron in the brain might be making things worse.”

Down syndrome and Alzheimer’s

Down syndrome is caused by having an extra third copy, or trisomy, of chromosome 21. This chromosome includes the gene for amyloid precursor protein, or APP, which is involved in the production of amyloid-beta (Aβ), the sticky protein that forms telltale plaques in the brains of people with Alzheimer’s disease.

Because people with Down syndrome have three copies of the APP gene instead of two, they tend to produce more of this protein. By the age of 60, about half of all people with Down syndrome show signs of Alzheimer’s disease, which is approximately 20 years earlier than in the general population.

“This makes understanding the biology of Down syndrome incredibly important for Alzheimer’s research,” said Finch, the study’s senior author.

Key findings point to ferroptosis

The research team studied donated brain tissue from individuals with Alzheimer’s, DSAD, and those without either diagnosis. They focused on the prefrontal cortex — an area of the brain involved in thinking, planning, and memory — and made several important discoveries:

  • Iron levels much higher in DSAD brains: Compared to the other groups, DSAD brains had twice the amount of iron in the prefrontal cortex. Scientists believe this buildup comes from tiny brain blood vessel leaks called microbleeds, which occur more frequently in DSAD than in Alzheimer’s and are correlated with higher amounts of APP.
  • More damage to lipid-rich cell membranes: Cell membranes are made of fatty compounds called lipids and can be easily damaged by chemical stress. In DSAD brains, the team found more byproducts of this type of damage, known as lipid peroxidation, compared to amounts in Alzheimer’s-only or control brains.
  • Weakened antioxidant defense systems: The team found that the activity of several key enzymes that protect the brain from oxidative damage and repair cell membranes was lower in DSAD brains, especially in areas of the cell membrane called lipid rafts.

Together, these findings indicate increased ferroptosis, a type of cell death characterised by iron-dependent lipid peroxidation, Thorwald explained: “Essentially, iron builds up, drives the oxidation that damages cell membranes, and overwhelms the cell’s ability to protect itself.”

Lipid rafts: a hotspot for brain changes

The researchers paid close attention to lipid rafts — tiny parts of the brain cell membrane that play crucial roles in cell signalling and regulate how proteins like APP are processed. They found that in DSAD brains, lipid rafts had much more oxidative damage and fewer protective enzymes compared to Alzheimer’s or healthy brains.

Notably, these lipid rafts also showed increased activity of the enzyme β-secretase, which interacts with APP to produce Aβ proteins. The combination of more damage and more Aβ production may promote the growth of amyloid plaques, thus speeding up Alzheimer’s progression in people with Down syndrome, Finch explained.

Rare Down syndrome variants offer insight

The researchers also studied rare cases of individuals with “mosaic” or “partial” Down syndrome, in which the third copy of chromosome 21 is only present in a smaller subset of the body’s cells. These individuals had lower levels of APP and iron in their brains and tended to live longer. In contrast, people with full trisomy 21 and DSAD had shorter lifespans and higher levels of brain damage.

“These cases really support the idea that the amount of APP — and the iron that comes with it — matters a lot in how the disease progresses,” Finch said.

Looking ahead

The team says their findings could help guide future treatments, especially for people with Down syndrome who are at high risk of Alzheimer’s. Early research in mice suggests that iron-chelating treatments, in which medicine binds to the metal ions and allows them to leave the body, may reduce indicators of Alzheimer’s pathology, Thorwald noted.

“Medications that remove iron from the brain or help strengthen antioxidant systems might offer new hope,” Thorwald said. “We’re now seeing how important it is to treat not just the amyloid plaques themselves but also the factors that may be hastening the development of those plaques.”

Source: University of Southern California

Categories : Exercise Neurodegenerative DiseasesTags :

Exercise Activates Cells that Protect Against Alzheimer’s

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Photo by Barbara Olsen on Pexels

Using advanced single-nuclei RNA sequencing (snRNA-seq) and a widely used preclinical model for Alzheimer’s disease, researchers from Mass General Brigham and collaborators at SUNY Upstate Medical University have identified specific brain cell types that responded most to exercise. These findings, which were validated in samples from humans, shed light on the connection between exercise and brain health and point to future drug targets. Results are published in Nature Neuroscience.

“While we’ve long known that exercise helps protect the brain, we didn’t fully understand which cells were responsible or how it worked at a molecular level,” said senior author Christiane Wrann, DVM, PhD, a neuroscientist at Massachusetts General Hospital. “Now, we have a detailed map of how exercise impacts each major cell type in the memory centre of the brain in Alzheimer’s disease.”

Brain support cells—astrocytes enriched in the protein cadherin-4 (CDH4)
Scientists identified a distinct subtype of brain support cells—astrocytes enriched in the protein cadherin-4 (CDH4), shown in magenta, that seem to protect nerve cells against cell death. In Alzheimer’s disease, these cells become less abundant, but exercise seems to strengthen them. (Image credit: Luis Moreira)

The study focused on a part of the hippocampus – a critical region for memory and learning that is damaged early in Alzheimer’s disease. The research team leveraged single-nuclei RNA sequencing, a relatively new technologies that allow researchers to look at activity at the molecular level in single cells for an in-depth understanding of diseases like Alzheimer’s.

The researchers exercised a common mouse model for Alzheimer’s disease using running wheels, which improved their memory compared to the sedentary counterparts. They then analysed gene activity across thousands of individual brain cells, finding that exercise changed activity both in microglia, a disease-associated population of brain cells, and in a specific type of neurovascular-associated astrocyte (NVA), newly discovered by the team, which are cells associated with blood vessels in the brain. Furthermore, the scientist identified the metabolic gene Atpif1 as an important regulator to create new neurons in the brain. “That we were able to modulate newborn neurons using our new target genes set underscores the promise our study,” said lead author Joana Da Rocha, PhD, a postdoctoral fellow working in Dr Wrann’s lab.

To ensure the findings were relevant to humans, the team validated their discoveries in a large dataset of human Alzheimer’s brain tissue, finding striking similarities.

“This work not only sheds light on how exercise benefits the brain but also uncovers potential cell-specific targets for future Alzheimer’s therapies,” said Nathan Tucker, a biostatistician at SUNY Upstate Medical University and co-senior of the study. “Our study offers a valuable resource for the scientific community investigating Alzheimer’s prevention and treatment.”

Source: Mass General Brigham