Alzheimer’s disease is known for its slow attack on neurons crucial to memory and cognition. But why are these particular neurons in aging brains so susceptible to the disease’s ravages, while others remain resilient?
A new study led by researchers at the Yale School of Medicine has found that susceptible neurons in the prefrontal cortex develop a “leak” in calcium storage with advancing age, they report April 8 in the journal Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association. This disruption of calcium storage in turns leads to accumulation of phosphorylated, or modified, tau proteins which cause the neurofibrillary tangles in the brain that are a hallmark of Alzheimer’s.
These changes occur slowly, building over many years, and can be seen within neurons in the brains of very old monkeys, the researchers report.
“Altered calcium signaling with advancing age is linked to early-stage tau pathology in the neurons that subserve higher cognition,” said corresponding author Amy Arnsten, the Albert E. Kent Professor of Neuroscience and professor of psychology and member of the Kavli Institute of Neuroscience at Yale University.
These vulnerable neurons face another problem. As they age, they tend to lose a key regulator of calcium signaling, a protein called calbindin, which protects neurons from calcium overload, and is abundant in the neurons of younger individuals.
“With age, these neurons face a double whammy, with an excessive calcium leak that initiates toxic actions, as well as diminished levels of the protectant, calbindin,” said Arnsten.
Neurons in the prefrontal cortex require relatively high levels of calcium to perform their cognitive operations, but the calcium must be tightly regulated. However, as regulation is lost with increasing age, neurons become susceptible to tau pathology and degeneration. Essentially, neurons “eat” themselves from within.
“Understanding these early pathological changes may provide strategies to slow or prevent disease progression,” Arnsten said.
The study is a collaboration between the labs of Arnsten and Angus Nairn at Yale; Dibyadeep Datta and Shannon N. Leslie are co-first authors of the research.
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Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.

When you think of ways to treat opioid use disorder, you might think methadone clinics and Narcotics Anonymous meetings. You probably don’t imagine stretches and strengthening exercises.
But Anne Swisher — professor at the West Virginia University School of Medicine — is working to address opioid misuse in an unconventional way: through physical therapy. She and her colleagues have enhanced physical therapy instruction at WVU to emphasize the profession’s role in preventing and treating opioid use disorder.
“Students have different interests and passions within the profession, and they find their niche,” said Swisher, a researcher and director of scholarship in the Division of Physical Therapy. “No matter what their passion is, there is a way they can make a difference, whether it’s by preventing people from starting down the road of opioids — by minimizing pain medication and doing movement interventions — or whether it’s by helping people in the recovery process become healthier overall.”
Swisher and her team devised a model to show doctor of physical therapy students how key topics in their curriculum — such as women’s health, pediatric care and sports therapy — could all address opioid use disorder in various ways.
Their model — which was published in rehabilitation journal Physical Therapy — is innovative because it goes beyond musculoskeletal issues and addresses how physical therapists can assist people across the lifespan, from neonatal to hospice settings. It also illustrates how physical therapists can help improve human movement across what Swisher calls the “whole addiction spectrum.”
“In our curriculum, our students learn about all of these different aspects — what to do with somebody who’s critically ill, the appropriate developmental milestones for children, how to help older people stay active — but it was really just a matter of connecting it all together,” she said.

Scientists could be a step closer to finding a way to reduce the impact of traumatic memories, according to a Texas A&M University study published recently in the journal Nature Neuroscience.
The report details a study by researchers from the Department of Psychological and Brain Sciences and the Institute for Neuroscience. Stephen Maren, professor of psychological and brain sciences, said the group’s findings suggest that procedures used by clinicians to indirectly reactivate traumatic memories render a window whereby those memories can be altered, or even erased completely.
In therapy, imaginal reminders are often used to safely retrieve traumatic memories of experiences. For example, Maren said a military veteran wounded by an improvised explosive device may be asked to re-experience trauma cues — like the lights and sounds of the explosion — without the negative consequences. The idea is that the fear responses can be dampened through this exposure therapy.
“The one major challenge is when you do the extinction procedures, it doesn’t erase the original trauma memory,” Maren said. “It’s always there and can bubble back up, which is what causes relapse for people who re-experience fear.”
With this in mind, the researchers hoped to answer whether they could isolate a memory and drive fear responses by reactivating it artificially — and potentially disrupt the original memory itself. Maren said their findings suggest that procedures currently used by clinicians to indirectly reactivate traumatic memories create an opportunity to change or eliminate them.
To do this, the researchers used a conditioning procedure in which a cue becomes indirectly associated with a fearful event. When the cue is presented later, it indirectly reactivates a memory of the event and increases activity in the hippocampus, a brain area important for memory.
The study showed that indirectly reactivating a contextual fear memory through re-exposure to the cue can make the memory vulnerable to disruption. Maren said further research is needed to answer if scientists can produce a permanent loss of the traumatic information.
Authors on the study are Maren, Reed L. Ressler, Travis D. Goode, Sohmee Kim and Karthik R. Ramanathan. This research was funded by the National Institutes of Health.
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Materials provided by Texas A&M University. Original written by Caitlin Clark. Note: Content may be edited for style and length.

Damage to the autism-associated gene Dyrk1a, sets off a cascade of problems in developing mouse brains, resulting in abnormal growth-factor signaling, undergrowth of neurons, smaller-than-average brain size, and, eventually, autism-like behaviors, a new study from Scripps Research, Florida, finds.
The study from neuroscientist Damon Page, PhD, describes a new mechanism underlying the brain undergrowth seen in individuals with Dyrk1a mutations. Page’s team used those insights to target the affected pathway with an existing medicine, a growth hormone. It restored normal brain growth in the Dyrk1a mutant mice, Page says.
“As of now, there’s simply no targeted treatments available for individuals with autism spectrum disorders caused by DYRK1A mutations,” Page says. “This represents a first step in evaluating a potential treatment that could be used in the clinic.”
Their study appears Thursday in the journal Biological Psychiatry.
To track the effects of missing Dyrk1a genes, Jenna Levy, the paper’s first author and a graduate student in Page’s lab, engineered mice to have one or two broken copies of Dyrk1a in their developing brain tissue. The brains of both sets of mice developed abnormally, she found, displaying decreased brain size and number of neurons, as well as reduced number of other brain cells.
Downstream effects
The scientists also conducted “unbiased” proteomic studies, to see if the mutant mice had abnormally high or low levels of other unknown proteins that might impact brain development. Using a technique called “high-resolution tandem mass spectrometry coupled to liquid chromatography,” they found that the Dyrk1a mutant mice had reduced levels of 56 cellular proteins, and increased levels of 33. Many of those were known autism risk genes, some implicated in sending growth signals, Levy says.

It’s one thing to decide among two or three snacks available at a friend’s house. But what do people do when they’re faced with a vending machine offering 36 different options?
A new study using eye-tracking technology suggests that the amount of time people spend looking at individual items may actually help them decide. Findings showed that people tended to choose snacks they spent more time looking at, sometimes even over snacks that they rated more highly.
“We could do pretty well predicting what people would choose based just on their ratings of the snacks available to them. But we could do an even better job by accounting for how much they looked at each item,” said Ian Krajbich, co-author of the study and associate professor of psychology and economics at The Ohio State University.
But the amount of time people spend looking at individual items isn’t the whole story of how people decide when they have many alternatives, Krajbich said.
“It’s a little more complicated than that,” he said.
Krajbich conducted the study with lead author Armin Thomas of Technische Universität Berlin and Felix Molter of Freie Universität Berlin. The research was published this week in the journal eLife.

The full assembly of human chromosome 8 is reported this week in Nature. While on the outside this chromosome looks typical, being neither short nor long or distinctive, its DNA content and arrangement are of interest in primate and human evolution, in several immune and developmental disorders, and in chromosome sequencing structure and function generally.
This linear assembly is a first for a human autosome — a chromosome not involved in sex determination. The entire sequence of chromosome 8 is 146,259,671 bases. The completed assembly fills in the gap of more than 3 million bases missing from the current reference genome.
The Nature paper is titled “The structure, function and evolution of a complete chromosome 8.”
One of several intriguing characteristics of chromosome 8 is a fast-evolving region, where the mutation rate appears to be highly accelerated in humans and human-like species, in contrast to the rest of the human genome.
While chromosome 8 offers some insights into evolution and human biology, the researchers point out that the complete assembly of all human chromosomes would be necessary to acquire a fuller picture.
An international team of scientists collaborated on the chromosome 8 assembly and analysis. The lead author of the paper is Glennis Logsdon, a postdoctoral fellow in genome sciences at the University of Washington School of Medicine in Seattle.

Powerful algorithms used by Netflix, Amazon and Facebook can ‘predict’ the biological language of cancer and neurodegenerative diseases like Alzheimer’s, scientists have found.
Big data produced during decades of research was fed into a computer language model to see if artificial intelligence can make more advanced discoveries than humans.
Academics based at St John’s College, University of Cambridge, found the machine-learning technology could decipher the ‘biological language’ of cancer, Alzheimer’s, and other neurodegenerative diseases.
Their ground-breaking study has been published in the scientific journal PNAS today (April 8 2021) and could be used in the future to ‘correct the grammatical mistakes inside cells that cause disease’.
Professor Tuomas Knowles, lead author of the paper and a Fellow at St John’s College, said: “Bringing machine-learning technology into research into neurodegenerative diseases and cancer is an absolute game-changer. Ultimately, the aim will be to use artificial intelligence to develop targeted drugs to dramatically ease symptoms or to prevent dementia happening at all.”
Every time Netflix recommends a series to watch or Facebook suggests someone to befriend, the platforms are using powerful machine-learning algorithms to make highly educated guesses about what people will do next. Voice assistants like Alexa and Siri can even recognise individual people and instantly ‘talk’ back to you.

Pioneering research led by experts from the University of Exeter’s Living Systems Institute has provided new insight into formation of the human embryo.
The team of researchers discovered an unique regenerative property of cells in the early human embryo.
The first tissue to form in the embryo of mammals is the trophectoderm, which goes on to connect with the uterus and make the placenta. Previous research in mice found that trophectoderm is only made once.
In the new study, however, the research team found that human early embryos are able to regenerate trophectoderm. They also showed that human embryonic stem cells grown in the laboratory can similarly continue to produce trophectoderm and placental cell types.
These findings show unexpected flexibility in human embryo development and may directly benefit assisted conception (IVF) treatments. In addition, being able to produce early human placental tissue opens a door to finding causes of infertility and miscarriage.
The study is published in the leading international peer-review journal Cell Stem Cell on Wednesday, April 7th 2021.
Dr Ge Guo, lead author of the study from the Living Systems Institute said: “We are very excited to discover that human embryonic stem cells can make every type of cell required to produce a new embryo.”
Professor Austin Smith, Director of the Living Systems Institute and co-author of the study added, said: “Before Dr Guo showed me her results, I did not imagine this should be possible. Her discovery changes our understanding of how the human embryo is made and what we may be able do with human embryonic stem cells”
Human naïve epiblast cells possess unrestricted lineage potential is published in Cell Stem Cell. The research was funded by the Medical Research Council (MRC) .
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Materials provided by University of Exeter. Note: Content may be edited for style and length.

Scientists have made a pivotal breakthrough in understanding the way in which cells communicate with each other.
A team of international researchers, including experts from the University of Exeter’s Living Systems Institute, has identified how signalling pathways of Wnt proteins — which orchestrate and control many cell developmental processes — operate on both molecular and cellular levels.
Various mechanisms exist for cells to communicate with each other, and many are essential for development. This information exchange between cells is often based on signalling proteins that activate specific intracellular signalling cascades to control cell behaviour at a distance.
Wnt proteins are produced by a relatively small group of cells and orchestrate cell proliferation and differentiation, but also cell movement and polarity of the neighbouring cells.
However, one of the most crucial functions of the Wnt signalling is patterning of the body axis — which essentially helps determine where the head and tail should form in in a developing tissue.
Previous research led by Professor Steffen Scholpp, from the Living Systems Institute, highlighted that thin finger-like protrusions, known as cytonemes, carry Wnts from the source cells to recipient cells.

A dysfunctional immune system significantly contributes to the development of cancer. Several therapeutic strategies to activate the immune system to target cancer cells have been approved to treat different types of cancer, including melanoma. However, some patients do not show beneficial clinical responses to these novel and very promising immunotherapies. In a new article published in Proceedings of the National Academy of Sciences of the United States of America, Moffitt Cancer Center researchers demonstrate how an important defect in STING gene expression in melanoma cells contributes to their evasion from immune cell detection and destruction.
Several different mechanisms have been discovered that allow cancer cells to avoid immune cell detection and destruction, including defective T cell function, losses in expression of key proteins on tumor cells and defective cell signaling in both immune and tumor cells. An important signaling pathway that contributes to interactions between tumor cells and immune cells is the interferon signaling pathway. The interferon pathway increases expression of molecules that allow tumor cells to be recognized and killed by immune cells. One of the key molecules in the interferon signaling pathway is STING, which is activated by the protein cGAS.
Moffitt researchers previously demonstrated that STING activity is commonly suppressed and altered in a subset of melanomas, which prevents the ability of these tumor cells to be targeted by the immune system. The research team wanted to further the understanding of the importance of alterations in STING signaling in melanoma and determine how STING expression becomes suppressed. They focused on a process called epigenetic modification during which methylation groups are added to the DNA regulatory regions of genes, resulting in genes being turned off.
The researchers performed a series of laboratory experiments and discovered that the DNA regulatory region of the STING gene is highly modified by methylation groups resulting in loss of STING gene expression in certain melanoma cell lines. Importantly, they confirmed these findings in patient clinical samples of early and late-stage melanomas and showed similar methylation events and loss of expression of the upstream STING regulator cGAS.
Next, the researchers demonstrated that it is possible to reactivate expression of STING and/or cGAS with a demethylating drug or genetic approaches that overcome methylation. These interventions successfully turned on STING functional activity, resulting in increased interferon levels when triggered by STING agonist drugs that enabled the melanoma cells to now be recognized by immune cells and targeted for destruction.
These findings demonstrate for the first time that a strategy to overcome STING gene methylation can restore interferon signaling and immune cell activity in melanoma and improve a cell-based immunotherapy when combined with STING agonist drugs.
“These studies show the critical importance of an intact STING pathway in melanomas for optimal T cell immunotherapy success, and how to overcome a notable STING defect in melanoma cases of gene hypermethylation by a combination therapy,” said James J. Mulé, Ph.D., senior author and associate center director for Translational Science at Moffitt. “Unless patients’ melanomas are pre-screened for intact versus defective STING, it is not at all surprising that clinical trials of STING agonists have, to date, uniformly failed.”
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Materials provided by H. Lee Moffitt Cancer Center & Research Institute. Note: Content may be edited for style and length.