When we think about the causes of neurological disorders and how to treat them, we think about targeting the brain. But is this the best or only way? Maybe not. New research by scientists at Baylor College of Medicine suggests that microbes in the gut may contribute to certain symptoms associated with complex neurological disorders. The findings, published in the journal Cell, also suggest that microbe-inspired therapies may one day help to treat them.
Dr. Mauro Costa-Mattioli, professor and Cullen Foundation Endowed Chair in neuroscience and director of the Memory and Brain Research Center at Baylor, discovered with his team that different abnormal behaviors are interdependently regulated by the host’s genes and microbiome. Specifically, the team found that in mouse models for neurodevelopmental disorders, hyperactivity is controlled by the host’s genetics, whereas social behavior deficits are mediated by the gut microbiome.
More importantly from a therapeutic perspective, they found that treatment with a specific microbe that promotes the production of compounds in the biopterin family in the gut or treatment with a metabolically active biopterin molecule improved the social behavior but not motor activity.
“We are the bearers of both host and microbial genes. While most of the focus has traditionally been in host genes, the gut microbiome, the community of microorganisms that live within us, is another important source of genetic information,” Costa-Mattioli said.
The work by Costa-Mattioli’s group offers a different way of thinking about neurological disorders in which both human and microbial genes interact with each other and contribute to the condition. Their findings also suggest that effective treatments would likely need to be directed at both the brain and the gut to fully address all symptoms. Additionally, they open the possibility that other complex conditions, such as cancer, diabetes, viral infection or other neurological disorders may have a microbiome component.
Brain-gut-microbiome crosstalk
“It’s very difficult to study these complex interactions in humans, so in this study, we worked with a mouse model for neurodevelopmental disorders in which the animals lacked both copies of the Cntnap2 gene (Cntnap2-/- mice),” said co-first author Sean Dooling, a Ph.D. candidate in molecular and human genetics in the Costa-Mattioli lab. “These mice presented with social deficits and hyperactivity, similar to those observed in autism spectrum disorders (ASD). In addition, these mice, like many people with ASD, also had changes in the bacteria that make up their microbiome compared to the mice without the genetic change.”

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Further experiments showed that modulating the gut microbiome improved the social behavior in the mutant mice, but did not alter their hyperactivity, indicating that the changes in the microbiome selectively contribute to the animals’ social behavior.
“We were able to separate the contribution of the microbiome and that of the animal’s genetic mutation on the behavioral changes,” Dooling said. “This shows that the gut microbiome shouldn’t be ignored as an important variable in studying health and disease.”
Equipped with this knowledge, the researchers dug deeper into the mechanism underlying the microbiome’s effect on the animal’s social deficits. Based on their previous work, the investigators treated the mice with the probiotic microbe, L. reuteri.
“We found that L. reuteri also can restore normal social behavior but cannot correct the hyperactivity in Cntnap2-/- mice,” said co-first author Dr. Shelly Buffington, a former postdoctoral fellow in the Costa-Mattioli lab and now an assistant professor at the University of Texas Medical Branch in Galveston.
However, the bigger surprise came when the investigators administered to the asocial mice a metabolite or compound they found was increased in the host’s gut by L. reuteri. They discovered that the animals’ social deficits also were improved after treating them with the metabolite instead of the bacteria.

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“This provides us with at least two possible ways to modulate the brain from the gut, with the bacteria or the bacteria-induced metabolite,” said Buffington.
Bacteria to heal your brain & beyond
Could this work inspire new breakthroughs in treating neurological disorders? While it is still too early to say for sure, the investigators are particularly excited about the translational implications of their findings. “Our work strengthens an emerging concept of a new frontier for the development of safe and effective therapeutics that target the gut microbiome with selective probiotic strains of bacteria or bacteria-inspired pharmaceuticals,” Buffington said.
“As we learn more about how these bacteria work, we will be able to more precisely and effectively leverage their power to help treat the brain and perhaps more,” Dooling added.
This research represents important step forward in the field as many disorders, especially those affecting the brain, remain very difficult to treat.
“Despite all the scientific advances and the promise of gene manipulation, it is still difficult to modulate human genes to treat diseases, but modulating our microbiome may be an interesting, noninvasive alternative,” said Costa-Mattioli. Indeed, L. reuteri currently is being tested in a clinical trial in Italy in children with autism, and Costa-Mattioli aims to start his own trial soon.
“In my wildest dreams, I could have never imagined that microbes in the gut could modulate behavior and brain function. To think now that microbial-based strategies may be a viable way to treat neurological dysfunction, is still wild, but very exciting.”

On December 6, 2016, a high-energy particle hurtled to Earth from outer space at close to the speed of light. The particle, an electron antineutrino, smashed into an electron deep inside the ice sheet at the South Pole. This collision produced a particle that quickly decayed into a shower of secondary particles, triggering the sensors of the IceCube Neutrino Observatory, a massive telescope buried in the Antarctic glacier.
IceCube had seen a Glashow resonance event, a phenomenon predicted by Nobel laureate physicist Sheldon Glashow in 1960. With this detection, scientists provided another confirmation of the Standard Model of particle physics. It also further demonstrated the ability of IceCube, which detects nearly massless particles called neutrinos using thousands of sensors embedded in the Antarctic ice, to do fundamental physics. The result was published March 10 in Nature.
Sheldon Glashow first proposed this resonance in 1960 when he was a postdoctoral researcher at what is today the Niels Bohr Institute in Copenhagen, Denmark. There, he wrote a paper in which he predicted that an antineutrino — a neutrino’s antimatter twin — could interact with an electron to produce an as-yet undiscovered particle through a process known as resonance. The key was that the antineutrino had to have a precise energy to produce this resonance.
When the proposed particle, the W-minus boson, was finally discovered in 1983, it turned out to be much heavier than what Glashow and his colleagues had expected back in 1960. The Glashow resonance would require a neutrino with an energy of 6.3 petaelectronvolts, almost 1,000 times more energetic than what CERN’s Large Hadron Collider is capable of producing. No human-made particle accelerator on Earth, current or planned, can create a neutrino with that much energy.
Yet the enormous energies of supermassive black holes at the centers of galaxies and other extreme cosmic events can generate particles with energies impossible to create on Earth. Such a phenomenon was likely responsible for the antineutrino that reached IceCube in 2016, which smashed into Earth with an energy of 6.3 PeV — precisely as Glashow’s theory predicted.
“When Glashow was a postdoc at Niels Bohr, he could never have imagined that his unconventional proposal for producing the W-minus boson would be realized by an antineutrino from a faraway galaxy crashing into Antarctic ice,” says Francis Halzen, principal investigator of IceCube and professor of physics at the University of Wisconsin-Madison, the headquarters of IceCube maintenance and operations.

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Since IceCube started full operation in May 2011, the observatory has detected hundreds of high-energy astrophysical neutrinos and has produced a number of significant results in particle astrophysics, including the discovery of an astrophysical neutrino flux in 2013 and the first identification of a source of astrophysical neutrinos in 2018. The Glashow resonance event is noteworthy because of its extremely high energy. It is only the third event detected by IceCube with an energy greater than 5 PeV.
This result was a collaborative effort achieved by a team of three scientists: Lu Lu from Chiba University in Japan, now at UW-Madison, Tianlu Yuan from UW-Madison, and Christian Haack from RWTH Aachen University, now at TU Munich.
The Glashow resonance detection is the first individual neutrino proven to be of astrophysical origin. It also demonstrates IceCube’s unique contributions to multimessenger astrophysics, which uses light, particles and gravitational waves to study the cosmos. The result also opens up a new chapter of neutrino astronomy because it starts to disentangle neutrinos from antineutrinos.
“Previous measurements have not been sensitive to the difference between neutrinos and antineutrinos, so this result is the first direct measurement of an antineutrino component of the astrophysical neutrino flux,” says Lu, one of the main analyzers of this paper.
“There are a number of properties of the astrophysical neutrinos’ sources that we cannot measure, like the physical size of the accelerator and the magnetic field strength in the acceleration region,” says Yuan, an assistant scientist at the Wisconsin IceCube Particle Astrophysics Center and another main analyzer. “If we can determine the neutrino-to-antineutrino ratio, we can directly investigate these properties.”
The result also demonstrates the value of international collaboration. IceCube is operated by over 400 scientists, engineers, and staff from 53 institutions in 12 countries, together known as the IceCube Collaboration. The main analyzers on this paper worked together across Asia, North America, and Europe.

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To confirm the detection and make a decisive measurement of the neutrino-to-antineutrino ratio, the IceCube Collaboration wants to see more Glashow resonances. A proposed expansion of the IceCube detector, IceCube-Gen2, would enable the scientists to make such measurements in a statistically significant way. The collaboration recently announced an upgrade of the detector that will be implemented over the next few years, the first step toward IceCube-Gen2.
Glashow, now an emeritus professor of physics at Boston University, echoes the need for more detections of his eponymous resonance events.
“To be absolutely sure, we should see another such event at the very same energy as the one that was seen,” he says. “So far there’s one, and someday there will be more.”
This work was supported in part by the National Science Foundation (grants OPP-1600823 and PHY-191360.

In the first study of the genomic architecture of the human placenta, scientists at the Wellcome Sanger Institute, the University of Cambridge and their collaborators have confirmed that the normal structure of the placenta is different to any other human organ and resembles that of a tumour, harbouring many of the same genetic mutations found in childhood cancers.
The study, published today (10 March 2021) in Nature, found evidence to support the theory of the placenta as a ‘dumping ground’ for genetic defects, whereas the fetus corrects or avoids these errors. The findings provide a clear rationale for studying the association between genetic aberrations and birth outcomes, in order to better understand problems such as premature birth and stillbirth.
In the earliest days of pregnancy, the fertilized egg implants into the wall of the uterus and begins dividing from one cell into many. Cells differentiate into various types of cell and some of them will form the placenta. Around week ten of pregnancy, the placenta begins to access the mother’s circulation, obtaining oxygen and nutrients for the fetus, removing waste products and regulating crucial hormones.
It has long been known that the placenta is different from other human organs. In one to two per cent of pregnancies, some placental cells have a different number of chromosomes to cells in the fetus — a genetic flaw that could be fatal to the fetus, but with which the placenta often functions reasonably normally.
Despite this genetic robustness, problems with the placenta are a major cause of harm to the mother and unborn child, such as growth restriction or even stillbirths.
This new study is the first high-resolution survey of the genomic architecture of the human placenta. Scientists at the Wellcome Sanger Institute and the University of Cambridge conducted whole genome sequencing of 86 biopsies and 106 microdissections from 42 placentas, with samples taken from different areas of each organ.

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The team discovered that each one of these biopsies was a genetically distinct ‘clonal expansion’ — a cell population descended from a single common ancestor — indicating a clear parallel between the formation of the human placenta and the development of a cancer.
Analysis also identified specific patterns of mutation that are commonly found in childhood cancers, such as neuroblastoma and rhabdomyosarcoma, with an even higher number of these mutations in the placenta than in the cancers themselves.
Professor Steve Charnock-Jones, a senior author of the study from the University of Cambridge, said: “Our study confirms for the first time that the placenta is organised differently to every other human organ, and in fact resembles a patchwork of tumours. The rates and patterns of genetic mutations were also incredibly high compared to other healthy human tissues.”
The team used phylogenetic analysis to retrace the evolution of cell lineages from the first cell divisions of the fertilised egg and found evidence to support the theory that the placenta tolerates major genetic flaws.
In one biopsy, the researchers observed three copies of chromosome 10 in each cell, two from the mother and one from the father, instead of the usual one copy from each parent. But other biopsies from the same placenta and from the fetus carried two copies of chromosome 10, both from the mother. A chromosomal copy number error such as this in any other tissue would be a major genetic flaw.
Professor Gordon Smith, a senior author of the study from the University of Cambridge, said: “It was fascinating to observe how such a serious genetic flaw as a chromosomal copy number error was ironed out by the baby but not by the placenta. This error would have been present in the fertilized egg. Yet derivative cell populations, and most importantly those that went on to form the child, had the correct number of copies of chromosome 10, whereas parts of the placenta failed to make this correction. The placenta also provided a clue that the baby had inherited both copies of the chromosome from one parent, which can itself be associated with problems.”
Now that the link between genetic aberrations in the placenta and birth outcomes has been established, further studies using larger sample sizes could help to uncover the causes of complications and diseases that arise during pregnancy.
Dr Sam Behjati, a senior author of the study from the Wellcome Sanger Institute, said: “The placenta is akin to the ‘wild west’ of the human genome, completely different in its structure from any other healthy human tissue. It helps to protect us from flaws in our genetic code, but equally there remains a high burden of disease associated with the placenta. Our findings provide a rationale for studying the association between genetic aberrations in the placenta and birth outcomes at the high resolution we deployed and at massive scale.”

When the body detects a pathogen, such as bacteria or viruses, it mounts an immune system response to fight this invader. In some people, the immune system overreacts, resulting in an overactive immune response that causes the body to injure itself, which may prove fatal in some cases.
Now, scientists from Nanyang Technological University, Singapore (NTU Singapore) have created a compound that could help to reduce this overactivation without impairing the body’s entire immune response.
An overactive immune system leads to many autoimmune disorders — when the immune system mistakenly attacks healthy tissues — such as rheumatoid arthritis and type 1 diabetes. More recently, it has also been linked to severe COVID-19 infections, in which immune-system signalling proteins ramp up to dangerous levels, leading to damage to the body’s own cells.
This compound designed by the NTU research team, called ASO-1, targets tyrosine kinase 2 (TYK2), a member from the Janus kinase (JAK) family of enzymes that play a key role in regulating the body’s immune response. A recent study led by the University of Edinburgh and published in the leading scientific journal Nature found that high levels of TYK2 have been associated with severe COVID-19 .
Through lab experiments using human cells grown in a dish, the NTU scientists found that ASO-1 potently reduced TYK2 levels over a sustained period and inhibited immune signalling pathways that have been associated with autoimmune disorders.
This points to the potential of the ASO-1 compound forming the basis for treatment of autoimmune conditions, said the team led by Professor Phan Anh Tuan from NTU Singapore’s School of Physical and Mathematical Sciences (SPMS).

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Professor Phan, who is also the interim director of the NTU Institute of Structural Biology, said: “Human genetic studies have suggested that deactivating TYK2 could provide protection against a broad range of autoimmune conditions such as rheumatoid arthritis, psoriasis, lupus, and type 1 diabetes.”
Dr Lim Kah Wai, NTU senior research fellow and co-lead author of the study, added: “With the UK-led study of critically ill COVID-19 patients published in Nature linking high TYK2 expression to severe COVID-19, ASO-1 could be a therapeutic agent worth investigating further. We are planning to conduct further pre-clinical work to validate its therapeutic potential.”
The findings were published in February in the scientific journal ImmunoHorizons, a publication of The American Association of Immunologists, and the research team has filed a patent for the compound they designed.
Targeting genetic material that leads to TYK2 production
A number of drugs that reduce inflammation resulting from an overactive immune response target the Janus kinase (JAK) family of four proteins: JAK1, JAK2, JAK3 and TYK2.

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Recently, TYK2 has emerged as researchers’ preferred target. As the structures of the four members are highly similar, it is important to selectively target TYK2 to limit unwanted side effects.
The ASO-1 compound designed by the NTU research team is an antisense oligonucleotide (ASO). ASOs are a type of RNA therapeutics — they target the messenger RNA (mRNA), which carries genetic instructions that cells ‘read’ to make proteins. ASO-1 is designed to bind to TYK2 mRNA, thus preventing cells from producing TYK2 protein.
The research team conducted lab experiments on human cell cultures and found ASO-1 to be highly potent and selective for TYK2, with no effect against the other JAK proteins. Dr Lim noted that this high potency of ASO-1 rivals that of recent ASO drug candidates that have advanced to clinical trials or have been approved for clinical use.
The NTU team discovered ASO-1 from over 200 potentially effective ASOs, which were designed based on their in-house expertise on nucleic acids.
The team has established an integrated platform spanning the design, synthesis, and cellular testing of RNA therapeutics. TYK2 stands among a range of therapeutic targets for immunology and cancer therapy, which is the primary focus of the team.
The NTU researchers plan to partner several academic collaborators to test ASO-1 in animal models and are open to industrial collaboration on the development of the ASO-1 compound towards clinical use.

Blood pressure measurements in children and adolescents should be taken from both arms after new research showed substantial differences could be seen depending on which arm was used.
The study, led by the Murdoch Children’s Research Institute (MCRI) and published in the Journal of Hypertension, found even a small difference in blood pressure measurements between arms could lead to a wrong diagnosis.
MCRI PhD candidate and study lead author Melanie Clarke said this was the first study worldwide to determine the size and frequency of inter-arm blood pressure differences in children and adolescents.
The study involved 118 participants, aged 7-18 years, recruited from a cardiology day clinic in Melbourne. It found in healthy children one in four had an inter-arm difference that could lead to misdiagnosis. This figure doubled in those with a history of aortic surgery, which is often performed in infants with congenital heart disease.
Ms Clarke said the high rates of misclassification occurred because the difference between a normal and hypertensive recording was so small.
“Misdiagnosis could occur when the blood pressure difference is greater than about 5 mmHg, but one in seven healthy children had a difference greater than 10 mmHg, which could lead to a failure to identify stage one or two hypertension,” she said.

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“Given blood pressure measured in a child’s right and left arm are often different, it’s important to take measurements in both arms to make a correct diagnosis. Accurate blood pressure assessment in kids is critical for identifying the potential risk for damage to the heart and blood vessels, which can lead to early-onset cardiovascular disease.”
High blood pressure is one of the primary risk factors for heart disease and stroke, the leading causes of death worldwide. Globally, an average of three children per school classroom have elevated blood pressure or hypertension (almost 14 per cent).
MCRI Associate Professor Jonathan Mynard said children with high blood pressure were more likely to develop hypertension as adults at a relatively young age, and the damage it caused to the heart and blood vessels started silently in childhood.
“Children with high blood pressure, many of whom appear to be healthy, have a greater risk of developing hypertension in adulthood, a major risk factor for cardiovascular disease,” he said.
The European Society of Hypertension and the American Academy of Pediatrics recommend blood pressure be measured in children and adolescents at least once a year. However, Associate Professor Mynard said in Australia it wasn’t common practice for GPs to measure blood pressure in children or in both arms.
“We know high blood pressure is common in adults but many people don’t realise how common it is in kids too,” he said. Parents can help by encouraging their kids to eat a healthy diet that is low in salt and sugary drinks, and high in fruit, vegetables, and whole grains, and to engage in lots of physical activity.
“More work needs to be done to draw attention to the problem of childhood hypertension and its long-term consequences. Australia would benefit from having its own set of clinical guidelines addressing high blood pressure in children, including how to obtain accurate measurements and avoid misclassification.”
Heart Foundation Chief Medical Advisor and cardiologist Professor Garry Jennings said: “There are good clinical reasons for measuring blood pressure in both arms in children and adolescents in the evaluation of hypertension and this study provides clear support for this approach.” Researchers from the University of Melbourne, The Royal Children’s Hospital and the Slippery Rock University in Pennsylvania also contributed to the findings.

Scientists from the Institute of Industrial Science at The University of Tokyo demonstrated how the adaptive immune system uses a method similar to reinforcement learning to control the immune reaction to repeat infections. This work may lead to significant improvements in vaccine development and interventions to boost the immune system.
In the human body, the adaptive immune system fights germs by remembering previous infections so it can respond quickly if the same pathogens return. This complex process depends on the cooperation of many cell types. Among these are T helpers, which assist by coordinating the response of other parts of the immune system — called effector cells — such as T killer and B cells. When an invading pathogen is detected, antigen presenting cells bring an identifying piece of the germ to a T cell. Certain T cells become activated and multiply many times in a process known as clonal selection. These clones then marshal a particular set of effector cells to battle the germs. Although the immune system has been extensively studied for decades, the “algorithm” used by T cells to optimize the response to threats is largely unknown.
Now, scientists at The University of Tokyo have used an artificial intelligence framework to show that the number of T helpers act like the “hidden layer” between inputs and outputs in an artificial neural network commonly used in adaptive learning. In this case, the antigens presented are the inputs, and the responding effector immune cells are the output.
“Just as a neural network can be trained in machine learning, we believe the immune network can reflect associations between antigen patterns and the effective responses to pathogens,” first author Takuya Kato says.
The main difference between the adaptive immune system compared with computer machine learning is that only the number of T helper cells of each type can be varied, as opposed to the connection weights between nodes in each layer. The team used computer simulations to predict the distribution of T cell abundances after undergoing adaptive learning. These values were found to agree with experimental data based on the genetic sequencing of actual T helper cells.
“Our theoretical framework may completely change our understanding of adaptive immunity as a real learning system,” says co-author Tetsuya Kobayashi. “This research can shed light on other complex adaptive systems, as well as ways to optimize vaccines to evoke a stronger immune response.”

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Materials provided by Institute of Industrial Science, The University of Tokyo. Note: Content may be edited for style and length.

In a study recently published in Nature Communications, scientists from The Novo Nordisk Foundation Center for Biosustainability (DTU) and Yale University have investigated how bacteria that are commonly found in sugarcane ethanol fermentation affect the industrial process. By closely studying the interactions between yeast and bacteria, it is suggested that the industry could improve both its total yield and the cost of the fermentation processes by paying more attention to the diversity of the microbial communities and choosing between good and bad bacteria.
The scientists dissected yeast-bacteria interactions in sugarcane ethanol fermentation by reconstituting every possible combination of the microbial community structure, covering approximately 80% of the biodiversity found in industrial processes, and especially one bacterium deserves extra attention: Lactobacillus amylovorus. But how come exactly this one doesn’t fall into the category of “the bad guys”? The main reason is that it produces a lot of the molecule acetaldehyde, which is used to feed yeast and thus helps it to grow. You could say that Lactobacillus amylovorus is more generous by nature and shares the meal, whereas many other bacteria involved in these processes prefer simply to steal the food.
“It works almost in the same way as a probiotic that shields the bad bacteria from entering into the system. And when this bacterium grows, it will grow in a way that is almost symbiotic with the yeast which is very beneficial for the industrial process,” says Felipe Lino, former PhD Student at The Novo Nordisk Foundation Center for Biosustainability and Global R & D Manager at Anheuser-Busch InBev.
Significant improvement of yield
Thus, companies could take advantage of selecting not only for an ideal yeast strain for production, as they started doing already in the 90’s, but to select for the best-suited bacteria as well, since it is completely impossible to get rid of bacteria that are hanging around no matter what. An effort that could turn out to pay dividends already in a short-term perspective.
By using this probiotic in a sugarcane ethanol fermentation, it is estimated that the fermentation yield could increase by three percent. While three percent can sound like a rather low number this is definitely not the case. According to Brazil’s Biofuels Annual 2019, Brazil’s total ethanol production in 2019 was 34.5 billion liters with domestic demand for 34 billion liters making the country the home to the largest fleet of cars that use ethanol derived from sugarcane as an alternative fuel to fossil fuel-based petroleum.
These numbers indicate that optimised fermentation processes hold great potential. One way to start ensuring more efficient industrial production of ethanol would be to apply more targeted approaches and shift away from a “one-size fits all” strategy where sulfuric acid treatment is used without further consideration to lower the pH and kill the bacteria to keep the population under a certain threshold. This would be beneficial both economically and environmentally, says Morten Sommer, Professor and Group Leader at The Novo Nordisk Foundation Center for Biosustainability.
“Instead of using a broad range of antibiotics, one should go for a more specific solution where you keep the good bacteria inside the fermenter. This is definitely a paradigm shift because you are not per definition fighting against all bacteria, since some of the bacteria are actually good and improve your final output significantly while also having a positive effect on production costs and the environmental footprint.”

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Materials provided by Technical University of Denmark. Original written by Anders Østerby Mønsted, Bernadette Maria Grant. Note: Content may be edited for style and length.

Newly published research has revealed a close link between proteins associated with Alzheimer’s disease and age-related sight loss. The findings could open the way to new treatments for patients with deteriorating vision and through this study, the scientists believe they could reduce the need for using animals in future research into blinding conditions.
Amyloid beta (AB) proteins are the primary driver of Alzheimer’s disease but also begin to collect in the retina as people get older. Donor eyes from patients who suffered from age-related macular degeneration (AMD), the most common cause of blindness amongst adults in the UK, have been shown to contain high levels of AB in their retinas.
This new study, published in the journal Cells, builds on previous research which shows that AB collects around a cell layer called the retinal pigment epithelium (RPE), to establish what damage these toxic proteins cause RPE cells.
The research team exposed RPE cells of normal mouse eyes and in culture to AB. The mouse model enabled the team to look at the effect the protein has in living eye tissue, using non-invasive imaging techniques that are used in ophthalmology clinics. Their findings showed that the mouse eyes developed retinal pathology that was strikingly similar to AMD in humans.
Dr Arjuna Ratnayaka, a Lecturer in Vision Sciences at the University of Southampton, who led the study said, “This was an important study which also showed that mouse numbers used for experiments of this kind can be significantly reduced in the future. We were able to develop a robust model to study AMD-like retinal pathology driven by AB without using transgenic animals, which are often used by researchers the field. Transgenic or genetically engineered mice can take up to a year and typically longer, before AB causes pathology in the retina, which we can achieve within two weeks. This reduces the need to develop more transgenic models and improves animal welfare.”
The investigators also used the cell models, which further reduced the use of mice in these experiments, to show that the toxic AB proteins entered RPE cells and rapidly collected in lysosomes, the waste disposal system for the cells. Whilst the cells performed their usual function of increasing enzymes within lysosomes to breakdown this unwanted cargo, the study found that around 85% of AB still remained within lysosomes, meaning that over time the toxic molecules would continue to accumulate inside RPE cells.
Furthermore, the researchers discovered that once lysosomes had been invaded by AB, around 20 percent fewer lysosomes were available to breakdown photoreceptor outer segments, a role they routinely perform as part of the daily visual cycle.
Dr Ratnayaka added, “This is a further indication of how cells in the eye can deteriorate over time because of these toxic molecules collecting inside RPE cells. This could be a new pathway that no-one has explored before. Our discoveries have also strengthened the link between diseases of the eye and the brain. The eye is part of the brain and we have shown how AB which is known to drive major neurological conditions such as Alzheimer’s disease can also causes significant damage to cells in retina.”
The researchers hope that one of the next steps could be for anti-amyloid beta drugs, previously trialled in Alzheimer’s patients, to be re-purposed and trialled as a possible treatment for age-related macular degeneration. As the regulators in the USA and the European Union have already given approval for many of these drugs, this is an area that could be explored relatively quickly.
The study may also help wider efforts to largely by-pass the use of animal experimentation where possible, so some aspects of testing new clinical treatments can transition directly from cell models to patients.
This research was funded by the National Centre for the Replacement Refinement & Reduction of animals in research (NC3Rs). Dr Katie Bates, Head of Research Funding at the NC3Rs said:
“This is an impactful study that demonstrates the scientific, practical and 3Rs benefits to studying AMD-like retinal pathology in vitro.”

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Materials provided by University of Southampton. Note: Content may be edited for style and length.