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

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.

“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

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

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