Tag Archives: #alzheimer

Researchers Uncovered the Early Assembly of Gamma-secretase, Linked to Development of Alzheimer (Neuroscience)

A research team led by Wim Annaert (VIB-KU Leuven) uncovered the early assembly of gamma-secretase, a protein complex linked to numerous cellular processes including the development of Alzheimer’s disease. In a first step, two dimeric subcomplexes are formed, which independently exit the ER and only afterwards assemble into a four-subunit complex. This ‘buckle up’ mechanism is thought to prevent premature assembly and activity. The new insights are very relevant, as gamma-secretase is an important potential therapeutic target for Alzheimer’s and other conditions.

An enzyme complex involved in plaque production

Gamma-secretase is best known as the enzyme that cleaves the amyloid precursor protein, generating a small peptide called amyloid beta, the main constituent of the plaques found in the brains of people affected by Alzheimer’s disease. Ever since the discovery of its implication in disease, gamma-secretase has been studied and tested as a potential therapeutic target, but its role in the body is much broader than producing amyloid.

We now know that gamma-secretase is a complex made up of four components, two of which have multiple homologues, resulting in variety of complexes with distinct subcellular distributions, providing a basis for substrate selectivity. All four gamma-secretase components are transmembrane proteins that are co-translationally inserted into the endoplasmic reticulum (ER). But how these four subunits get assembled in such stable enzyme complexes remained unknown until now. 

Dissecting the assembly line

The Annaert lab at the VIB-KU Leuven Center for Brain & Disease Research is specialized in membrane trafficking and has a long track record of studying the gamma-secretase complex. By combining biochemistry and high-resolution imaging, they have now uncovered the early steps of the gamma-secretase assembly process. 

“To dissect the assembly steps, we used a method developed by Randy Schekman of UC Berkeley (who won the Noble Prize in Medicine in 2013), and with whom we collaborated on this endeavor. This approach unveiled that in fact dimers of two out of the four subunits are formed in the ER, in this way preventing the premature breakdown of individual subunits,” says Wim Annaert. “These dimers only get fully assembled into gamma-secretase complexes shortly thereafter, between ER-exit and their transition to the Golgi complex.”

Only fully assembled complexes are transported through the Golgi onto their final destination in different cellular compartments. 

Interestingly, the dimer assembly signature remains visible in the high-resolution structure of gamma-secretase, suggesting a ‘buckle up model’ for dimer assembly: one side of the dimers act as ‘buckles’, while the other side functions as the belt through interactions keeping the full complex in place.

“This ‘buckle up’ mechanism could prevent the untimely processing of substrates,” says Annaert. “Given the broad range of substrates and pathways controlled by gamma-secretase –from developmental processes to cancer and Alzheimer, the precise tuning of this assembly process allows for further spatiotemporal regulation of gamma-secretase activity.” 

The insights are extremely relevant, as problems during complex assembly may also have a significant impact on the many physiological and pathological processes regulated by gamma-secretase.

Featured image: In gamma-secratese assembly, dimers are preformed in the ER and buckle up in a full complex after ER exit. © VIB

Provided by VIB

Spinal Fluid Biomarkers Detect Neurodegeneration, Alzheimer’s Disease in Living Patients (Neuroscience)

Alzheimer’s Disease and other forms of neurodegeneration can be identified using a combination of biomarkers in cerebrospinal fluid of living patients, Penn researchers find

Alzheimer’s disease and related diseases can still only be confirmed in deceased patients’ brains via autopsy. Even so, the development of biomarkers can give patients and their families answers during life: Alzheimer’s disease can be accurately detected via peptides and proteins in a patient’s cerebrospinal fluids (CSF), which can be collected through a lumbar puncture and tested while the patient is alive. In 2018, a new framework suggested combining three Alzheimer’s disease biomarkers in CSF – pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N), collectively called ATN. According to recent research from the Perelman School of Medicine at the University of Pennsylvania, the ATN framework can be extended to detect another neurodegenerative condition: frontotemporal degeneration.

Patients with frontotemporal degeneration can experience a range of symptoms, including behavioral changes, executive dysfunction, and language impairments. Distinguishing frontotemporal degeneration from Alzheimer’s disease can be a challenge for clinicians: the symptoms of frontotemporal degeneration can sometimes overlap with Alzheimer’s disease, and a subset of patients can even have both pathologies. Biomarkers can fill the gap by providing evidence of whether Alzheimer’s pathology underlies a patient’s symptoms.

“CSF biomarkers work similarly to a pregnancy test, offering a simple positive or negative result when enough of a substance is detected. But like a pregnancy test, biomarkers for Alzheimer’s disease can provide false negatives or positives,” said lead investigator Katheryn A.Q. Cousins, PhD, a research associate in the Frontotemporal Degeneration Center in the Department of Neurology at Penn Medicine. “Alzheimer’s is a diverse disease, and it is common for other conditions to also be present in the brain. The ATN framework may provide a more complete look at a person’s diagnosis and give us a much richer understanding of not only Alzheimer’s disease, but other co-occurring neurodegenerative conditions. However, to accomplish this, additional biomarkers that can detect other neurodegenerative conditions are critically needed.”

The findings, published in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association, show that ATN incorporating neurofilament light chain (NfL) may provide a more accurate and precise diagnosis for patients with frontotemporal degeneration. NfL is a protein abundant in the brain, whose levels increase as degeneration progresses. Cousins’ work shows that CSF NfL may be a more accurate marker of neurodegeneration for patients with frontotemporal degeneration, including for Alzheimer’s disease.

“While the ATN framework is very exciting and offers much opportunity for patients with Alzheimer’s disease, these biomarkers don’t capture every case of the disease. We want to be able to detect and treat every patient with neurodegenerative disease as early as possible, and more research is needed to fully understand how biofluids track with the disease process,” said Cousins. “I am eager to conduct additional research into which patients might be missed by these markers, what they have in common, and what causes the pathological and clinical differences in the disease.”

This study was funded by the Swedish Research Council (2018-02532); the European Research Council, (681712); Swedish State Support for Clinical Research (ALFGBG-720931); the Alzheimer Drug Discovery Foundation (201809-2016862); the Swedish Alzheimer Foundation, (AF-742881); European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236); and the Alzheimer’s Association Research Fellowship (AARF-16-44368).

Provided by Penn Medicine

Researchers Identify Signaling Molecule That May Help Prevent Alzheimer’s Disease (Neuroscience)

Interleukin-3 may reprogram immune responses in the brain that cause cell death and lead to dementia.

New research in humans and mice identifies a particular signaling molecule that can help modify inflammation and the immune system to protect against Alzheimer’s disease. The work, which was led by investigators at Massachusetts General Hospital (MGH), is published in Nature.

Cognitive decline associated with Alzheimer’s disease develops when neurons begin to die. “Neuron death can be caused by improper immune responses and excessive neuroinflammation–or inflammation in the brain–triggered by high levels of amyloid beta deposits and tau tangles, two hallmarks of Alzheimer’s disease,” explains the paper’s co-senior author Filip Swirski, PhD, who conducted the work while a principal investigator in the Center for Systems Biology at MGH.

“Once neurons start dying in increasing amounts, brain cells called microglia and astrocytes–which are normally nurturing cells that clean up debris–become activated to cause neuroinflammation in an attempt to protect the brain. They are evolutionarily programmed to wipe out a brain region where there is excess neuronal cell death because it may be due to an infection, which must be stopped from spreading,” explains co-senior author Rudolph Tanzi, PhD, co-director of the McCance Center for Brain Health at MGH.

In the case of Alzheimer’s disease, the neuronal cell death brought on by amyloid beta deposits and tau tangles activates this response. “As neuroinflammation ensues, the amount of cell death is at least 10 times higher than that which was caused by plaques and tangles,” says Tanzi. “In fact, without the induction of neuroinflammation, there would be no symptoms of dementia. We know this from ‘resilient’ brains, in which there are lots of plaques and tangles in an individual’s brain but no symptoms at death because there was minimal or no neuroinflammation.” Tanzi provides an analogy, noting that amyloid beta is the “match” that lights the spreading “brushfires” of tangles, but only when this leads to increasing numbers of “forest fires” through neuroinflammation that is activated by microglia and astrocytes does one lose enough neurons to suffer cognitive decline and dementia.

This new study in Nature revealed that a subset of astrocytes actually tries to put out the fire by releasing a molecule called interleukin-3 (IL-3), which then converts killer microglial cells back into nurturing and protective cells that no longer wipe out neurons and instead focus on cleaning out amyloid beta deposits and tau tangles.

“There may be important clinical implications to knowing that astrocytes talk to microglia via IL-3 to educate the microglia and help them decrease the severity of Alzheimer’s disease,” says Swirski. “We can now think about how to use IL-3 to not only help curb the neuroinflammation that carries out the bulk of neuronal cell death in Alzheimer’s disease, but also to entice microglia to once again take on the beneficial task of clearing away the deposits and tangles that are the initiating pathology of Alzheimer’s disease.”

“It was surprising to find IL-3 in the brain,” says first author Cameron McAlpine, PhD, then an instructor in the Center for Systems Biology. “Our findings suggest that communication between astrocytes and microglia, via IL-3, is an important mechanism that wards off Alzheimer’s disease by instructing microglia to adapt protective functions. With further study, IL-3 signaling may provide a new therapeutic opportunity to combat neurological diseases.”

Tanzi is vice chair of Neurology and director of the Genetics and Aging Research Unit at MGH. Swirski is director of the Cardiovascular Research Institute and professor of Medicine (Cardiology) and Diagnostic Molecular and Interventional Radiology at the Icahn School of Medicine at Mount Sinai in New York City. McAlpine is assistant professor of Medicine (Cardiology) and Neuroscience at the Icahn School of Medicine. Study co-authors include Joseph Park, Ana Griciuc, Eunhee Kim, Se Hoon Choi, PhD, Yoshiko Iwamoto, Máté G. Kiss, Kathleen A. Christie, Claudio Vinegoni, PhD, Wolfram C. Poller, John E. Mindur, Christopher T. Chan, Shun He, Henrike Janssen, Lai Ping Wong, Jeffrey Downey, Sumnima Singh, Atsushi Anzai, PhD, Florian Kahles, MD, Mehdi Jorfi, Paolo Fumene Feruglio, Ruslan I. Sadreyev, Ralph Weissleder, MD, PhD, Benjamin P. Kleinstiver, and Matthias Nahrendorf, MD, PhD.

The study was funded by the Cure Alzheimer’s Fund, the National Institutes of Health, the Patricia and Scott Eston MGH Research Scholar, a Canadian Institutes of Health Research Banting Fellowship, and a Kirschstein National Research Service Award Individual Predoctoral Fellowship.

Featured image credit: gettyimages

Reference: McAlpine, C.S., Park, J., Griciuc, A. et al. Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease. Nature (2021). https://doi.org/10.1038/s41586-021-03734-6

Provided by Massachusetts General Hospital

Study Points To FDA-approved Drugs That Have Potential to Slow or Reverse Brain Damage (Neuroscience)

A research team at Washington University School of Medicine in St. Louis has identified potential new treatment targets for Alzheimer’s disease, as well as existing drugs that have therapeutic potential against these targets.

The potential targets are defective proteins that lead to the buildup of amyloid in the brain, contributing to the onset of problems with memory and thinking that are the hallmark of Alzheimer’s. The 15 existing drugs identified by the researchers have been approved by the Food and Drug Administration (FDA) for other purposes, providing the possibility of clinical trials that could begin sooner than is typical, according to the researchers.

In addition, the experiments yielded seven drugs that may be useful for treating faulty proteins linked to Parkinson’s disease, six for stroke and one for amyotrophic lateral sclerosis (ALS). The new study, funded by the National Institute on Aging of the National Institutes of Health (NIH), is published July 8 in the journal Nature Neuroscience.

Scientists have worked for decades to develop treatments for Alzheimer’s by targeting genes rooted in the disease process but have had little success. That approach has led to several dead ends because many of those genes don’t fundamentally alter proteins at work in the brain. The new study takes a different approach, by focusing on proteins in the brain, and other tissues, whose function has been altered.

Cruchaga© WUSTL

“In this study, we used human samples and the latest technologies to better understand the biology of Alzheimer’s disease,” said principal investigator Carlos Cruchaga, PhD, the Barbara Burton and Reuben M. Morriss III Professor of Neurology and a professor of psychiatry. “Using Alzheimer’s disease samples, we’ve been able to identify new genes, druggable targets and FDA-approved compounds that interact with those targets to potentially slow or reverse the progress of Alzheimer’s.”

The scientists focused on protein levels in the brain, cerebrospinal fluid (CSF) and blood plasma of people with and without Alzheimer’s disease. Some of the proteins were made by genes previously linked to Alzheimer’s risk, while others were made by genes not previously connected to the disease. After identifying the proteins, the researchers compared their results to several databases of existing drugs that affect those proteins.

“They are FDA-approved, and all of the safety data on the drugs is available,” said Cruchaga. “With what is already known about the safety of these drugs, we may be able to jump directly to clinical trials.”

Cruchaga said the team’s focus on protein levels in key tissues has certain advantages over prior efforts to identify genes linked to Alzheimer’s.

“The classic genetic studies of Alzheimer’s have attempted to correlate genetic mutations with disease, but we know that genes carry the instructions to build proteins and that diseases such as Alzheimer’s occur when those protein levels get too high or too low,” Cruchaga explained. “To understand the biology of Alzheimer’s disease, we should look at proteins rather than only at genes.”

As an example, Cruchaga pointed to the APOE gene, which was first linked to Alzheimer’s risk decades ago. But even after all this time, it still has not been clear how that gene contributes to the disease.

“In this study, we were able to see that APOE alters levels of several proteins in brain tissue and CSF,” Cruchaga said. “We also saw changes in proteins linked to another gene called TREM2 that was associated with Alzheimer’s risk more recently. Understanding how the protein levels are affected by these risk genes is helping us to identify pathways that lead to disease.”

Past research has helped identify about 50 genetic signals linked to Alzheimer’s, but only a handful of the genes responsible for those signals have been found. Cruchaga said that focusing on protein levels in tissue may help reveal what’s happening with the other 40-plus genetic signals that appear to be connected to Alzheimer’s risk.

The researchers analyzed proteins and genes from brain tissue, cerebrospinal fluid and blood plasma from samples gathered from 1,537 people in the U.S. The samples are stored at the Knight Alzheimer’s Disease Research Center at Washington University. Half of the samples came from people with a clinical diagnosis of Alzheimer’s disease; the other half came from study participants who are considered cognitively normal.

The researchers measured protein levels in the samples from the brain, CSF and plasma. Using statistical techniques, they then connected the protein levels to disease. There were 274 proteins linked to disease in study subjects’ CSF, 127 in blood plasma and 32 in brain tissue.

They applied those findings and machine learning techniques to distinguish among the protein differences and zero in on some of the proteins that contribute to damage that leads to Alzheimer’s.

“We have targets — although I’m not saying all of these targets are going to work or that all of the compounds we identified are going to stop the progress of the disease — but we have a real hypothesis,” Cruchaga said. “And we expect it may be possible to move from these genetic studies into real clinical trials quickly. That’s a big jump.”

This work was supported by the National Institute on Aging of the National Institutes of Health (NIH). Grant numbers R01 AG044546, P01 AG003991, Rf1 AG053303, R01 AG058501, U01 AG58922, RF1 AG058501, and R01 AG057777. Additional support from the Alzheimer’s Association. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991 and P01 AG026276.

Featured image: A research team at Washington University School of Medicine in St. Louis has identified potential new treatment targets for Alzheimer’s disease, as well as existing drugs with therapeutic potential. The targets are defective proteins, and the 15 existing drugs identified by the researchers have been approved by the Food and Drug Administration (FDA) for other purposes, providing the possibility of clinical trials that could begin sooner than is typical, according to the researchers. © CRUCHAGA LAB

Reference: Yang C, et al. Genomic and multi-tissue proteomic integration for understanding the genetic architecture of neurological diseases. Nature Neuroscience, published online July 8, 2021.

Provided by Washington University School of Medicine in St Louis

Structural Model that Explains How Charged Biopolymers Enhance Protein Clustering in Amyloid Diseases (Neuroscience)

Amyloid diseases, including Alzheimer’s, Parkinson’s, type-2 diabetes and other life-threatening diseases, involve pathologic deposits of normally soluble proteins or peptides as insoluble amyloid fibrils. When this happens in vital organs, such as the brain, kidney, liver and heart, it causes organ damage and, if left untreated, death. Unfortunately, the available treatment options are very limited.

Now a new study from BUSM researchers improves our understanding of how heparan sulfate and related biopolymers such as heparin, which is perhaps best known as a blood thinner, can promote amyloid deposition in various organs.

The researchers explain how charged biopolymers that cover the cell surfaces, such as heparan sulfate proteoglycans, trigger the formation of pathologic amyloids in deadly human diseases including Alzheimer’s disease, chronic traumatic encephalopathy, inflammation-linked amyloidosis and many others. “Heparan sulfate has long been known to accelerate amyloid aggregation in diverse proteins. Why this happens was unclear. We proposed the first detailed structural model that shows how heparan sulfate can aid protein aggregation in amyloid,” explained corresponding author Olga Gursky, PhD, professor of physiology and biophysics.

According to the researchers, molecules such as heparan sulfate are not innocent bystanders but, rather, active participants in amyloid deposition in the body. “Interactions of these molecules with amyloid have been proposed as therapeutic targets. By understanding how charged biopolymers interact with amyloid aggregates on a molecular level, we can begin to design inhibitors to block these pathologic interactions,” said Emily Lewkowicz, PhD student in biophysics and the lead author of this study.

The researchers used spectroscopy and electron microscopy to explore protein-heparin interactions. This included proteins such as oxidized human apoA-I, which forms amyloid in cardiovascular disease. Their analysis showed that heparin speeds up amyloid nucleation and growth by this and other proteins. To explain why this happens, they then performed computational studies using atomic structures of amyloid fibrils and found that patient-derived amyloids contain bound heparin-like molecules associated with deadly human diseases such as Alzheimer’s or chronic traumatic encephalopathy.

Amyloid diseases are incurable disorders that afflict hundreds of millions worldwide and represent a major public health challenge of the 21st century. Research such as this will help guide targeted drug design for these deadly diseases. “Therapeutic targeting of amyloidoses requires a clear understanding of factors that promote or prevent amyloid deposition. This research brings us one step closer to designing amyloid-specific therapies,” added Lewkowicz.

These findings appear online in the journal Trends in Biochemical Sciences (TiBS, Cell Press).

This work was supported by the NIH grants GM067260 and GM135158.

Reference: Emily Lewkowicz, Shobini Jayaraman, Olga Gursky, Protein Amyloid Cofactors: Charged Side-Chain Arrays Meet Their Match?, Trends in Biochemical Sciences, 2021, , ISSN 0968-0004, https://doi.org/10.1016/j.tibs.2021.05.003. (https://www.sciencedirect.com/science/article/pii/S0968000421001055)

Provided by BU School of Medicine

Toxicity of Protein Involved in Alzheimer’s Triggered by a Chemical ‘Switch’ (Neuroscience)

Spotlight on amino acids causing tau protein toxicity might lead to new therapies

Researchers from Tokyo Metropolitan University have discovered that a specific chemical feature of a key protein known as tau may cause it to accumulate in the brain and trigger illnesses like Alzheimer’s. They found that disulfide bonds on certain amino acids act to stabilize tau and cause it to accumulate, an effect that got worse with increased oxidative stress. The identification of chemical targets triggering tau accumulation may lead to breakthrough treatments.

The tau protein is key to the healthy function of biological cells. It helps form and stabilize microtubules, the thin filaments that crisscross cell interiors to help keep them structurally rigid and provide ‘highways’ to shuttle molecules between organelles. However, when they are not formed correctly, they can accumulate and form sticky clumps. In the brain, these aggregates block the firing of neurons and cause a wide range of neurodegenerative diseases known as tauopathies, one of which is Alzheimer’s disease. It is vastly important that scientists find the ‘switch’ that transforms tau from an indispensable part of cell function to a deadly pathology.

A team led by Associate Professor Kanae Ando of Tokyo Metropolitan University has been using model organisms like the Drosophila fruit fly to uncover how specific features of the tau protein cause it to stop working properly. Flies can be genetically altered to express the same tau protein as in humans. By systematically modifying parts of the gene encoding for tau, they have been trying to pinpoint how certain features of mutant tau proteins affect their behavior.

In their most recent work, they found that alterations to amino acid residues in the protein known as cysteines in two different locations (C291 and C322) had a drastic effect on the amount and toxicity of tau. In a further breakthrough, the team pinned down the specific chemical feature responsible for making them toxic to normal cell function, that is, disulfide bonds formed by these cysteine groups. The toxic accumulation of tau got worse when cells were put in an environment with elevated levels of reactive oxygen species, as thiol groups on the cysteines were oxidized to form disulfide links. Biochemical environments with elevated oxidative stress are similar to those seen in patients with tauopathies. The co-expression of antioxidants to counter this effect helped natural processes clear away tau proteins, resulting in dramatically lower tau levels.

The team hope that knowledge of exactly which chemical groups are responsible for tau toxicity may lead to novel therapies which reduce or prevent tau accumulation, helping sufferers of tauopathies around the world.

This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (Brain Protein Aging and Dementia Control) [JSPS KAKENHI Grant number 17H05703], a research award from the Hoan-sha Foundation, the Takeda Science Foundation, a research award from the Japan Foundation for Aging and Health, a Grant-in-Aid for Scientific Research on Challenging Research (Exploratory) [JSPS KAKENHI Grant number 309 19K21593], and a Grant-in-Aid for Scientific Research on Innovative Areas (Brain Protein Aging and Dementia Control) [JSPS KAKENHI Grant number 26117004].

Featured image: Tau proteins with cysteine groups bearing thiol groups (S) undergo chemical changes under oxidative stress to form disulfide bonds, making a toxic mutant of the tau protein that can aggregate. These go on to cause neural degeneration. Antioxidants can help reduce these back to thiols; these normal tau proteins can then be naturally cleared away by the cell. © Tokyo Metropolitan University

Reference: Taro Saito, Tomoki Chiku, Mikiko Oka, Satoko Wada-Kakuda, Mika Nobuhara, Toshiya Oba, Kanako Shinno, Saori Abe, Akiko Asada, Akio Sumioka, Akihiko Takashima, Tomohiro Miyasaka, Kanae Ando, Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo, Human Molecular Genetics, 2021;, ddab162, https://doi.org/10.1093/hmg/ddab162

Provided by Tokyo Metropolitan University

Non-invasive Potential Treatment For Alzheimer’s Disease (Psychiatry)

Ultrasound can overcome some of the detrimental effects of ageing and dementia without the need to cross the blood-brain barrier, Queensland Brain Institute researchers have found.

Professor Jürgen Götz led a multidisciplinary team at QBI’s Clem Jones Centre for Ageing Dementia Research who showed low-intensity ultrasound effectively restored cognition without opening the barrier in mice models.

The findings provide a potential new avenue for the non-invasive technology and will help clinicians tailor medical treatments that consider an individual’s disease progression and cognitive decline.

Ultrasound shows restoration to cognition

“Historically, we have been using ultrasound together with small gas-filled bubbles to open the almost-impenetrable blood-brain barrier and get therapeutics from the bloodstream into the brain,” Professor Götz said.

The new research involved a designated control group who received ultrasound without the barrier-opening microbubbles.

“The entire research team was surprised by the remarkable restoration in cognition,” he said.

“We conclude therapeutic ultrasound is a non-invasive way to enhance cognition in the elderly.”

Ageing is associated with impaired cognition and a reduction in the learning induced plasticity of the signalling between neurons called long-term potentiation (LTP).

Dual role a benefit in fight against Alzheimer’s

Dr Daniel Blackmore, senior postdoctoral researcher on the team, said the new research aimed to use ultrasound to restore LTP and improved spatial learning in aged mice. 

Professor Götz said the brain was “not particularly accessible”, but ultrasound provided a tool for overcoming challenges like the blood-brain barrier.

“Using ultrasound could enhance cognition independently of clearing amyloid and tau, which form plaques and tangles in people with Alzheimer’s disease,” he said.

“Microbubbles will continue to be used in combination with ultrasound in ongoing Alzheimer’s research.”

About 400,000 people in Australia have dementia and numbers are projected to increase to one million by 2050, with ageing the single biggest risk factor.

Ageing questions improve dementia research

Previous research has shown the long-term safety of ultrasound technology and that pathological changes and cognitive deficits could be improved by using ultrasound to treat Alzheimer’s disease. 

Professor Götz said there were still questions about the differences between normal “physiological” ageing and the “pathological” ageing that happens in Alzheimer’s disease.

‘’We believe there may be some overlap between physiological and pathological ageing in the brain and the potential for this to be corrected with ultrasound is meaningful for those living with Alzheimer’s disease,” he said.

‘’We are taking these findings and implementing them in our Alzheimer’s research as we go forward to clinical trials.’’

Professor Götz’s research team aims to understand how brain diseases begin and their progression at molecular and cellular levels in the hope of ultimately developing therapies.

The research has been published in Nature journal Molecular Psychiatry.

Featured image: Professor Jürgen Götz led a Queensland Brain Institute team who showed low-intensity ultrasound effectively restored cognition without the need to cross the blood-brain barrier. © Queensland Brain Institute, The University of Queensland

Reference: Blackmore, D.G., Turpin, F., Palliyaguru, T. et al. Low-intensity ultrasound restores long-term potentiation and memory in senescent mice through pleiotropic mechanisms including NMDAR signaling. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01129-7

Provided by University of Queensland

Roughness of Retinal Layers, A New Alzheimer’s Biomarker (Neuroscience)

Over recent years, the retina has established its position as one of the most promising biomarkers for the early diagnosis of Alzheimer’s. Moving on from the debate as to the retina becoming thinner or thicker, researchers from the Universidad Complutense de Madrid and Hospital Clínico San Carlos are focusing their attention on the roughness of the ten retinal layers.

The study, published in Scientific Reports, “proves innovative” in three aspects according to José Manuel Ramírez, Director of the IIORC (Ramón Castroviejo Institute of Ophthalmologic Research) at the UCM. “This is the first study to propose studying the roughness of the retina and its ten constituent layers. They have devised a mathematical method to measure the degree of wrinkling, through the fractal dimension, and have discovered that in some layers of the retina these measurements indicate that wrinkling begins at very early stages of Alzheimer’s disease,” explains the IIORC expert.

To undertake the study, launched six years ago, the researchers developed computer programs allowing them to separate each layer of the retina. Following this subdivision, the problem which arose was how to distinguish the roughness of one layer from that of the neighbouring layers.

“As each is in contact with the others, the wrinkling of one layer is transmitted to the adjacent layers, and their roughness becomes blurred. The solution was to flatten each layer mathematically on each side and study the roughness remaining on the other side,” indicates Lucía Jáñez, the lead author of the publication.

Software development to calculate roughness

The second problem faced in the research was to find a procedure to measure roughness. “The solution lay in calculating the fractal dimension of the side of each retinal layer studied,” explains Luis Jáñez, researcher at the UCM’s ITC (Institute of Knowledge Technology).

“A flat surface has only two dimensions: length and width, but if it is folded or wrinkled it progressively takes on body and begins to appear a three-dimensional solid object. The fractal dimension adopts fractional values between 2 and 3, and so is suitable to measure the degree of wrinkling of retinal layers,” he adds.

The final step taken by the group was to incorporate the technology they had developed within the Optical Coherence Tomography (OCT) currently available on the market, using mathematical analysis to express this in software which calculates the roughness of each retinal layer, and establishes the boundary between health/illness.

For the patient, this is a simple, quick and low-cost test. “No prior preparation is required. They simply turn up for an ophthalmology appointment, sit facing the machine and spend about 4 seconds looking at a dot of light inside: that generates the OCT image. The analysis of the roughness of the image is performed by a computer program in less than one minute,” the ITC researcher indicates.

After a decade working in this field, researchers understand how the eyesight of patients with Alzheimer’s evolves, and the changes in retinal thickness. “From now on, with this new technique we can research how to use retinal roughness to monitor and ascertain the stage of Alzheimer’s disease,” predicts the IIORC researcher Elena Salobrar García.

As well as being used in Alzheimer’s, the methods they have developed could be applied in studying other diseases, such as ALS or Parkinson’s, “the effects of which on the retina we are now beginning to understand. As well as contributing to advances in neuroscience, this might also be useful in ophthalmology,” concludes Omar Bachtoula, researcher at the UCM Psychology Faculty.

Reference: Jáñez-García, L., Bachtoula, O., Salobrar-García, E. et al. Roughness of retinal layers in Alzheimer’s disease. Sci Rep 11, 11804 (2021). https://doi.org/10.1038/s41598-021-91097-3

Provided by UCM

P-glycoprotein Removes Alzheimer’s-associated Toxin From The Brain (Neuroscience)

Discovery could lead to new Alzheimer’s treatment

A team of SMU biological scientists has confirmed that P-glycoprotein (P-gp) has the ability to remove a toxin from the brain that is associated with Alzheimer’s disease.    

The finding could lead to new treatments for the disease that affects nearly 6 million Americans. It was that hope that motivated lead researchers James W. McCormick and Lauren Ammerman to pursue the research as SMU graduate students after they both lost a grandmother to the disease while at SMU. 

In the Alzheimer’s brain, abnormal levels of amyloid-β proteins clump together to form plaques that collect between neurons and can disrupt cell function. This is believed to be one of the key factors that triggers memory loss, confusion and other common symptoms from Alzheimer’s disease. 

“We were able to demonstrate both computationally and experimentally that P-gp, a critical toxin pump in the body, is able to transport this amyloid-β protein,” said John Wise, associate professor in the SMU Department of Biological Sciences and co-author of the study published in PLOS ONE.

“If you could find a way to induce more P-glycoprotein in the protective blood-brain barrier for people who are susceptible to Alzheimer’s disease, perhaps they could take such a treatment and it would help postpone or prevent the onset of the disease,” he said. Wise stressed that the theory needs more research. 

The SMU (Southern Methodist University) study also provides strong evidence for the first time that P-gp may be able to pump out much larger toxins than previously believed.  

(A) The first frame of SMU’s simulation shows amyloid-β bound to the drug binding domains of P-gp. (B) The final frame of the same simulation shows P-gp pushing an amyloid protein through the cell membrane to outside the cell.  © SMU

P-gp is nature’s way of removing toxins from cells. Similar to how a sump pump in your house removes water from the basement, P-gp swallows harmful drugs or toxins within the cell and then spits them back outside the cell.

“You find P-gp wherever the body is looking to protect an organ from toxins, and the brain is no exception,” explained co-author Pia Vogel, SMU professor and director of SMU’s Center for Drug Discovery, Design and Delivery

Amyloid-β’s large size created questions about whether P-glycoprotein could actually inhale it and pump it back out.   

“Amyloid-β is maybe five times bigger than the small, drug-like molecules that P-glycoproteins are well-known to move. It would be like taking New York pizza and trying to stuff that whole slice in your mouth and swallow it,” Wise said.

The fact that P-gp appears to be able to do just that “greatly expands the possible range of things that P-gp can transport, which opens the possibility that it may interact with other factors that were previously thought impossible,” said McCormick, a former SMU graduate student in biological sciences. 

The research was personal

SMU researchers might never have investigated the link between P-gp and amyloid-β proteins if not for McCormick’s dogged pursuit of the connection. The Ph.D. student, who graduated in 2017, had seen preliminary work suggesting that P-gp might play a role in pulling amyloid protein out of the brain and asked his faculty advisors, Vogel and Wise, if he could take some time to check it out. 

The professors concede they first tried to discourage him because they were more focused on P-gp’s role in creating resistance to chemotherapy in cancer patients. However, McCormick was “passionate,” about figuring out if P-gp might be able to shield someone from getting Alzheimer’s, Vogel said.   

He devoted hours of his own time to use a computer-generated model of P-glycoprotein that he and Wise created. The model allows researchers to dock nearly any drug to the P-gp protein and observe how it would behave in P-gp’s “pump.” Vogel, Wise and other SMU scientists have been studying the protein for years to identify compounds that might reverse chemotherapy failure in aggressive cancers. 

McCormick completed the computational work with the help of his fiancé, Ammerman, who got her Ph.D in biology from SMU in May.

Together, they ran multiple simulations of the P-gp protein using SMU’s high performance computer, ManeFrame II, and found that each time, P-gp was able to “swallow” amyloid-β proteins and push them out of cells.  

“For the scientist in me, it was just absolutely amazing that this pump could consume something that big,” Vogel said. “John [Wise] and I did not predict that would be possible.”

Two in vitro experiments confirmed the computational work

The researchers conducted two experiments in the lab to confirm the computational results.  

In one experiment, Ammerman used lab-purchased amyloid-β proteins that had been dyed fluorescent green, allowing them to be easily spotted easily in a microscope. In multiple trials, Ammerman exposed human cells to these amyloid-β proteins. She used two types of human cells — one where P-gp was strongly expressed and one where P-gp was not. This allowed Ammerman to test the difference between the two and see if P-gp was pumping amyloid-β out.       

The amyloid proteins were clearly shown to be pushed out of the human cells that had overexpressed P-gp in them, supporting the theory that P-gp removes amyloid proteins on contact. 

Another in vitro experiment reached the same conclusion from a different direction. Former graduate student Gang (Mike) Chen worked in SMU’s Center for Drug Discovery, Design and Delivery to show that an Alzheimer’s-linked amyloid-β caused changes in the P-gp’s usage of adenosine triphosphate (ATP), indicating that there was a physical interaction between the two. 

ATP hydrolysis produces the energy that P-gp uses to transport toxins or drugs out of the cell. When no toxins are present, P-gp’s rate of ATP stays pretty low. When challenged with transporting cargo, P-gp’s ATP hydrolysis activity usually increases quite dramatically.

“Even though our work can’t help our grandparents, I hope that it might help others in the future,” Ammerman said. “The more we know, the more power we have – and researchers after us – to address and target these devastating diseases.”

Featured image: Lauren Ammerman and James McCormick, who are getting married in November, sought to do research on Alzheimer’s disease after both SMU graduate students lost a grandmother to the disease. © SMU

Reference: McCormick JW, Ammerman L, Chen G, Vogel PD, Wise JG (2021) Transport of Alzheimer’s associated amyloid-β catalyzed by P-glycoprotein. PLoS ONE 16(4): e0250371. doi:10.1371/journal.pone.0250371

Provided by SMU