Cleaning up the aging brain: Scientists restore brain's trash disposal system

Alzheimer's, Parkinson's, and other neurological disorders can be seen as "dirty brain" diseases, where the brain struggles to clear out harmful waste. Aging is a key risk factor because, as we grow older, our brain's ability to remove toxic buildup slows down. However, new research in mice demonstrates that it's possible to reverse age-related effects and restore the brain's waste-clearing process.

"This research shows that restoring cervical lymph vessel function can substantially rescue the slower removal of waste from the brain associated with age," said Douglas Kelley, PhD, a professor of Mechanical Engineering in the University of Rochester Hajim School of Engineering and Applied Sciences. "Moreover, this was accomplished with a drug already being used clinically, offering a potential treatment strategy." Kelley is one of the lead authors of the study, which appears in the journal Nature Aging, along with Maiken Nedergaard, MD, DMSc, co-director the University's Center for Translational Neuromedicine.

First described by Nedergaard and her colleagues in 2012, the glymphatic system is the brain's unique waste removal process that uses cerebrospinal fluid (CSF) to wash away excess proteins generated by energy hungry neurons and other cells in the brain during normal activity. This discovery pointed the way for potential new approaches to treat diseases commonly associated with the accumulation of protein waste in the brain, such Alzheimer's (beta amyloid and tau) and Parkinson's (alpha-synuclein). In healthy and young brains, the glymphatic system does a good job of flushing away these toxic proteins, however, as we age, this system slows, setting the stage for these diseases.

A network of tiny pumps draws waste from the brain

Once laden with protein waste, CSF in the skull needs to make its way to the lymphatic system and ultimately the kidneys, where it is processed along with the body's other waste. The new research combines advanced imaging and particle tracking techniques to describe for the first time in detail the route via the cervical lymph vessels in the neck through which half of dirty CSF exits the brain.

In addition to measuring the flow of CSF, the researchers were able observe and record the pulsing of lymph vessels in the neck that helps draw CSF out of the brain. "Unlike the cardiovascular system which has one big pump, the heart, fluid in the lymphatic system is instead transported by a network of tiny pumps," said Kelley. These microscopic pumps, called lymphangions, have valves to prevent backflow and are strung together, one after another, to form lymph vessels.

The researchers found that as the mice aged, the frequency of contractions decreased, and the valves failed. As a result, the speed of dirty CSF flowing out of the brains of older mice was 63 percent slower compared to younger animals.

Known drug restarts flow of brain cleaning fluids

The team then set out to see if they could revive the lymphangions and identified a drug called prostaglandin F2α, a hormone-like compound commonly used medically to induce labor and known to aid smooth muscle contraction. The lymphangions are lined with smooth muscle cells, and when the researchers applied the drug to the cervical lymph vessels in older mice, the frequency of contractions and the flow of dirty CSF from the brain both increased, returning to a level of efficiency found in younger mice.

"These vessels are conveniently located near the surface of the skin, we know they are important, and we now know how to accelerate function," said Kelley. "One can see how this approach, perhaps combined with other interventions, could be the basis for future therapies for these diseases."

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Scientists define new type of memory loss in older adults

Researchers at Mayo Clinic have established new criteria for a memory-loss syndrome in older adults that specifically impacts the brain's limbic system. It can often be mistaken for Alzheimer's disease. The good news: Limbic-predominant Amnestic Neurodegenerative Syndrome, or LANS, progresses more slowly and has a better prognosis, and is now more clearly defined for doctors working to find answers for memory loss patients.

Prior to the researchers developing clinical criteria published in the journal Brain Communications, the hallmarks of the syndrome could be confirmed only by examining brain tissue after a person's death. The proposed criteria provide a framework for neurologists and other experts to classify the condition in patients living with symptoms, offering a more precise diagnosis and potential treatments. They consider factors such as age, severity of memory impairment, brain scans, and biomarkers indicating the deposits of specific proteins in the brain.

The criteria were developed and validated using data from more than 200 participants in databases for the Mayo Clinic Alzheimer's Disease Research Center, the Mayo Clinic Study of Aging and the Alzheimer's Disease Neuroimaging Initiative.

Understanding the condition will lead to better management of symptoms and more tailored therapies for patients suffering from this type of cognitive decline, distinct from Alzheimer's disease, says David T. Jones, M.D., a Mayo Clinic neurologist and senior author of the study.

"In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer's disease, but when you look at their brain imaging or biomarkers, it's clear they don't have Alzheimer's. Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers," Jones says. "This research creates a precise framework that other medical professionals can use to care for their patients. It has major implications for treatment decisions, including amyloid-lowering drugs and new clinical trials, and counseling on their prognosis, genetics and other factors."

Decades of work to understand and classify different types of dementia is ongoing, says Nick Corriveau-Lecavalier, Ph.D., the paper's first author. These findings build upon scientists' continued efforts to untangle neurological conditions that often have similar symptoms or can occur simultaneously, but can have drastically different treatments and prognoses.

"Historically, you might see someone in their 80s with memory problems and think they may have Alzheimer's disease, and that is often how it's being thought of today," Corriveau-Lecavalier says. "With this paper, we are describing a different syndrome that happens much later in life. Often, the symptoms are restricted to memory and will not progress to impact other cognitive domains, so the prognosis is better than with Alzheimer's disease."

Without signs of Alzheimer's disease, the researchers looked at the involvement of one possible culprit -- a buildup of a protein called TDP-43 in the limbic system that scientists have found in the autopsied brain tissue of older adults. Researchers have classified the build-up of these protein deposits as limbic-predominant age-related TDP-43 encephalopathy, or LATE. These protein deposits could be associated with the newly defined memory loss syndrome, but there are also other likely causes and more research is needed, the authors say.

With clinical criteria established by Jones, Corriveau-Lecavalier and co-authors, practitioners could soon diagnose LANS in patients so those living with memory loss might better understand options for treatment and potential progression of the disease, opening doors for research to further illuminate the characteristics of the disease.

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Researchers identify gene involved in neuronal vulnerability in Alzheimer's disease

Early stages of neurodegenerative disorders are characterized by the accumulation of proteins in discrete populations of brain cells and degeneration of these cells. For most diseases, this selective vulnerability pattern is unexplained, yet it could yield major insight into pathological mechanisms. Alzheimer's disease (AD), the world-leading cause of dementia, is defined by the appearance of two hallmark pathological lesions, amyloid plaques (extracellular aggregates of Aβ peptides) and neurofibrillary tangles (intracellular aggregates of hyperphosphorylated tau, or NFTs). While plaques are widespread in the neocortex and hippocampus, NFTs follow a well-defined regional pattern that starts in principal neurons from the entorhinal cortex.

In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers have identified a gene they believe may lead to the degeneration of the neurons that are most vulnerable to AD.

"We are trying to understand why certain neurons in the brain are particularly vulnerable during the earliest stages of AD. Why they accumulate and degenerate very early is unknown. We believe elucidating this vulnerability would allow for a new therapeutic avenue for AD," said corresponding author Jean-Pierre Roussarie, PhD, assistant professor of anatomy & neurobiology at the school.

In collaboration with leading computational genomic experts from Rice University, the BU researchers along with co-corresponding author, Patricia Rodriguez-Rodriguez, PhD, from Karolinska Institute, used cutting-edge analysis tools with machine learning to identify the gene DEK as possibly responsible for vulnerability of entorhinal cortex neurons.

They injected viruses into the entorhinal cortex of experimental models and neurons grown in the lab to manipulate levels of the DEK gene.

When they reduced the levels of the DEK gene, vulnerable neurons started to accumulate tau and to degenerate.

According to the researchers, preventing these neurons from degeneration by targeting DEK or proteins that collaborate with DEK, would prevent patients from developing memories loss and would curtail the disease before it spreads to larger areas of the brain.

"Given that entorhinal cortex neurons are necessary for the formation of new memories and since they are so vulnerable and the first to die, this explains why the first symptom of AD is the inability to form new memories," said Roussarie.

The researchers believe these findings are the first step in understanding how these fragile neurons die, yet they hope to uncover additional genes to fully understand what leads to the death of critical memory-forming neurons.

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Researchers 3D-print functional human brain tissue

A team of University of Wisconsin-Madison scientists has developed the first 3D-printed brain tissue that can grow and function like typical brain tissue.

It's an achievement with important implications for scientists studying the brain and working on treatments for a broad range of neurological and neurodevelopmental disorders, such as Alzheimer's and Parkinson's disease.

"This could be a hugely powerful model to help us understand how brain cells and parts of the brain communicate in humans," says Su-Chun Zhang, professor of neuroscience and neurology at UW-Madison's Waisman Center.

"It could change the way we look at stem cell biology, neuroscience, and the pathogenesis of many neurological and psychiatric disorders."

Printing methods have limited the success of previous attempts to print brain tissue, according to Zhang and Yuanwei Yan, a scientist in Zhang's lab.

The group behind the new 3D-printing process described their method today in the journal Cell Stem Cell.

Instead of using the traditional 3D-printing approach, stacking layers vertically, the researchers went horizontally.

They situated brain cells, neurons grown from induced pluripotent stem cells, in a softer "bio-ink" gel than previous attempts had employed.

"The tissue still has enough structure to hold together but it is soft enough to allow the neurons to grow into each other and start talking to each other," Zhang says.

The cells are laid next to each other like pencils laid next to each other on a tabletop.

"Our tissue stays relatively thin and this makes it easy for the neurons to get enough oxygen and enough nutrients from the growth media," Yan says.

The results speak for themselves -- which is to say, the cells can speak to each other.

The printed cells reach through the medium to form connections inside each printed layer as well as across layers, forming networks comparable to human brains.

The neurons communicate, send signals, interact with each other through neurotransmitters, and even form proper networks with support cells that were added to the printed tissue.

"We printed the cerebral cortex and the striatum and what we found was quite striking," Zhang says.

"Even when we printed different cells belonging to different parts of the brain, they were still able to talk to each other in a very special and specific way."

The printing technique offers precision -- control over the types and arrangement of cells -- not found in brain organoids, miniature organs used to study brains.

The organoids grow with less organization and control.

"Our lab is very special in that we are able to produce pretty much any type of neurons at any time. Then we can piece them together at almost any time and in whatever way we like," Zhang says.

"Because we can print the tissue by design, we can have a defined system to look at how our human brain network operates. We can look very specifically at how the nerve cells talk to each other under certain conditions because we can print exactly what we want."

That specificity provides flexibility. The printed brain tissue could be used to study signaling between cells in Down syndrome, interactions between healthy tissue and neighboring tissue affected by Alzheimer's, testing new drug candidates, or even watching the brain grow.

"In the past, we have often looked at one thing at a time, which means we often miss some critical components. Our brain operates in networks. We want to print brain tissue this way because cells do not operate by themselves. They talk to each other. This is how our brain works and it has to be studied all together like this to truly understand it," Zhang says.

"Our brain tissue could be used to study almost every major aspect of what many people at the Waisman Center are working on. It can be used to look at the molecular mechanisms underlying brain development, human development, developmental disabilities, neurodegenerative disorders, and more."

The new printing technique should also be accessible to many labs.

It does not require special bio-printing equipment or culturing methods to keep the tissue healthy, and can be studied in depth with microscopes, standard imaging techniques and electrodes already common in the field.

The researchers would like to explore the potential of specialization, though, further improving their bio-ink and refining their equipment to allow for specific orientations of cells within their printed tissue..

"Right now, our printer is a benchtop commercialized one," Yan says.

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Serotonin loss may contribute to cognitive decline in the early stages of Alzheimer's disease

Comparing PET scans of more than 90 adults with and without mild cognitive impairment (MCI), Johns Hopkins Medicine researchers say relatively lower levels of the so-called "happiness" chemical, serotonin, in parts of the brain of those with MCI may play a role in memory problems including Alzheimer's disease.

The findings, first published online Sept. 13 in the Journal of Alzheimer's Disease, lend support to growing evidence that measurable changes in the brain happen in people with mild memory problems long before an Alzheimer's diagnosis, and may offer novel targets for treatments to slow or stop disease progression.

"The study shows that people with mild cognitive impairment already display loss of the serotonin transporter. This measure that reflects serotonin degeneration is associated with problems with memory, even when we take into account in our statistical model MRI measures of neurodegeneration and PET measures of the amyloid protein that are associated with Alzheimer's Disease," says Gwenn Smith, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

MCI describes the diagnostic stage between normal brain function in aging and Alzheimer's Disease (AD). Symptoms of MCI include frequent forgetfulness of recent events, word finding difficulty, and loss of the sense of smell.

Those with MCI may stay in this stage indefinitely, or progress to more severe forms of cognitive deficits, giving urgency to the search for predictive markers, and possible early prevention interventions, investigators say.

The investigators cautioned that their study showed a correlation between lower serotonin transporter levels and memory problems in MCI, and was not designed to show causation or the role of serotonin in the progression from MCI to AD. To answer these questions, further research is needed to study over time healthy controls and individuals with MCI to demonstrate the role of serotonin in disease progression.

For the study, the Hopkins scientists recruited 49 volunteers with MCI, and 45 healthy adults ages 55 and older who underwent an MRI to measure changes in brain structure and two positron emission tomography (PET) scans of their brains at Johns Hopkins between 2009 and 2022.

The research team used PET scans to look specifically at the serotonin transporter -- a neurotransmitter, or brain chemical long associated with positive mood, appetite and sleep -- and to look at the amyloid-beta protein (Aβ) distribution in the brain.

Aβ is thought to play a central role in the pathology of AD. Studies in mice done at Johns Hopkins have shown that serotonin degeneration occurs before the development of widespread beta-amyloid deposits in the brain.

Loss of serotonin is often associated with depression, anxiety, and psychological disorders.

Researchers found that MCI patients had lower levels of the serotonin transporter, and higher levels of Aβ than healthy controls.

The MCI patients had up to 25% lower serotonin transporter levels in cortical and limbic regions than healthy controls.

In particular, they report, lower serotonin transporter levels were found in cortical, limbic, and subcortical regions of the brains in those with MCI, areas specifically responsible for executive function, emotion, and memory.

"The correlation we observed between lower serotonin transporters and memory problems in MCI is important because we may have identified a brain chemical that we can safely target that may improve cognitive deficits and, potentially, depressive symptoms," says Smith.

"If we can show that serotonin loss over time is directly involved in the transition from MCI to AD, recently developed antidepressant medications may be an effective way to improve memory deficits and depressive symptoms and thus, may be a powerful way forward to slow disease progression."

Researchers say future studies include longitudinal follow up of individuals with MCI to compare serotonin degeneration to the increase in and Aβ levels, as well as the increase in levels of the Tau protein that is also associated with AD compared to healthy adults.

They are also studying multi-modal antidepressant drugs to treat depression and memory deficits in hopes of mitigating and halting symptoms.

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How sleep deprivation can harm the brain

Not only does a lack of sleep make you feel awful, research has shown it impairs the brain. What's more, sleep loss over long periods can even increase risk for Alzheimer's and other neurological diseases. Researchers want to understand how sleep deprivation causes this harm. In a new study in ACS' Journal of Proteome Research, a team working with mice has identified a protective protein whose level declines with sleep deprivation, leading to neuronal death.

Studies indicate that lack of sleep leads to neurological damage in the hippocampus, a part of the brain involved in learning and memory. To better understand the changes responsible for this effect, scientists have begun examining shifts in the abundance of proteins and RNA, which contains genetically encoded instructions derived from DNA. In this way, previous studies have identified some factors linking sleep loss to damage; however, researchers haven't generally confirmed they play a role in cognitive function within larger animal populations. So, Fuyi Xu, Jia Mi and their colleagues set out to further explore how sleep loss damages the brain and to corroborate their findings.

To start off, the researchers evaluated how well mice navigated a simple maze and learned to recognize new objects after having been sleep deprived for two days. They then extracted the proteins in the animals' hippocampi and identified those whose abundance changed. Then, to further narrow the possibilities, they looked at data linking these proteins to maze performance in related strains of mice that had not experienced sleep deprivation.

This approach led the researchers to pleiotrophin (PTN), which declined in the sleep-deprived mice. Through an analysis of RNA, the team identified the molecular pathway by which a loss of PTN causes cells in the hippocampus to die. When they looked at genetic studies in humans, they found that PTN is implicated in Alzheimer's and other neurodegenerative diseases. This research has uncovered a new mechanism by which sleep protects brain function, according to the researchers, who also note that PTN levels could serve as an indicator of cognitive impairment resulting from insomnia.

From Science Daily

New study shows anti-inflammatory drugs as a promising target for Alzheimer's disease

A recent study from the lab of the University of Kentucky's Sanders-Brown Center on Aging Director Linda Van Eldik, Ph.D., has been published in PLOS ONE. The work centers around the idea that various anti-inflammatory drugs could be effective treatments for Alzheimer's disease (AD). This study focused on a protein known as p38. Many labs have been working with this protein as a potential target for drug development to treat Alzheimer's disease and other conditions with neuroinflammatory dysfunction.

Van Eldik and her team used genetic techniques to stop the production of p38 in the major immune cell type within the brain, the microglia. They tested the effects of this in an early-stage mouse model of AD to determine whether it would alter the trajectory of amyloid plaque formation, a major component of AD pathology. While the plaques themselves were not affected, the amount of microglia in proximity to these plaques was decreased, suggesting that suppression of microglial p38 may affect their interactions with aspects of AD pathology.

Some classes of anti-inflammatory drugs include p38 inhibitors, which are currently under clinical development and have shown encouraging results during recent human clinical trials. However, it is still not clear when during the disease process these p38 inhibitors should be administered and whether long-term suppression of p38 is harmful. The findings reported by the Van Eldik lab indicate that early inhibition of p38 may be able to alter interactions between brain immune cells and AD pathology, and they suggest that long-term suppression of p38 does not cause noticeable adverse effects.

From Science Daily

Artificial neural networks learn better when they spend time not learning at all

Depending on age, humans need 7 to 13 hours of sleep per 24 hours. During this time, a lot happens: Heart rate, breathing and metabolism ebb and flow; hormone levels adjust; the body relaxes. Not so much in the brain.

"The brain is very busy when we sleep, repeating what we have learned during the day," said Maxim Bazhenov, PhD, professor of medicine and a sleep researcher at University of California San Diego School of Medicine. "Sleep helps reorganize memories and presents them in the most efficient way."

In previous published work, Bazhenov and colleagues have reported how sleep builds rational memory, the ability to remember arbitrary or indirect associations between objects, people or events, and protects against forgetting old memories.

Artificial neural networks leverage the architecture of the human brain to improve numerous technologies and systems, from basic science and medicine to finance and social media. In some ways, they have achieved superhuman performance, such as computational speed, but they fail in one key aspect: When artificial neural networks learn sequentially, new information overwrites previous information, a phenomenon called catastrophic forgetting.

"In contrast, the human brain learns continuously and incorporates new data into existing knowledge," said Bazhenov, "and it typically learns best when new training is interleaved with periods of sleep for memory consolidation."

Writing in the November 18, 2022 issue of PLOS Computational Biology, senior author Bazhenov and colleagues discuss how biological models may help mitigate the threat of catastrophic forgetting in artificial neural networks, boosting their utility across a spectrum of research interests.

The scientists used spiking neural networks that artificially mimic natural neural systems: Instead of information being communicated continuously, it is transmitted as discrete events (spikes) at certain time points.

They found that when the spiking networks were trained on a new task, but with occasional off-line periods that mimicked sleep, catastrophic forgetting was mitigated. Like the human brain, said the study authors, "sleep" for the networks allowed them to replay old memories without explicitly using old training data.

Memories are represented in the human brain by patterns of synaptic weight -- the strength or amplitude of a connection between two neurons.

"When we learn new information," said Bazhenov, "neurons fire in specific order and this increases synapses between them. During sleep, the spiking patterns learned during our awake state are repeated spontaneously. It's called reactivation or replay.

"Synaptic plasticity, the capacity to be altered or molded, is still in place during sleep and it can further enhance synaptic weight patterns that represent the memory, helping to prevent forgetting or to enable transfer of knowledge from old to new tasks."

When Bazhenov and colleagues applied this approach to artificial neural networks, they found that it helped the networks avoid catastrophic forgetting.

"It meant that these networks could learn continuously, like humans or animals. Understanding how human brain processes information during sleep can help to augment memory in human subjects. Augmenting sleep rhythms can lead to better memory.

"In other projects, we use computer models to develop optimal strategies to apply stimulation during sleep, such as auditory tones, that enhance sleep rhythms and improve learning. This may be particularly important when memory is non-optimal, such as when memory declines in aging or in some conditions like Alzheimer's disease."

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Beer hops compounds could help protect against Alzheimer's disease

Beer is one of the oldest and most popular beverages in the world, with some people loving and others hating the distinct, bitter taste of the hops used to flavor its many varieties. But an especially "hoppy" brew might have unique health benefits. Recent research published in ACS Chemical Neuroscience reports that chemicals extracted from hop flowers can, in lab dishes, inhibit the clumping of amyloid beta proteins, which is associated with Alzheimer's disease (AD).

AD is a debilitating neurodegenerative disease, often marked by memory loss and personality changes in older adults. Part of the difficulty in treating the disease is the time lag between the start of underlying biochemical processes and the onset of symptoms, with several years separating them. This means that irreversible damage to the nervous system occurs before one even realizes they may have the disease. Accordingly, preventative strategies and therapeutics that can intervene before symptoms appear are of increasing interest.

One of these strategies involves "nutraceuticals," or foods that have some type of medicinal or nutritional function. The hop flowers used to flavor beers have been explored as one of these potential nutraceuticals, with previous studies suggesting that the plant could interfere with the accumulation of amyloid beta proteins associated with AD. So, Cristina Airoldi, Alessandro Palmioli and colleagues wanted to investigate which chemical compounds in hops had this effect.

To identify these compounds, the researchers created and characterized extracts of four common varieties of hops using a method similar to that used in the brewing process. In tests, they found that the extracts had antioxidant properties and could prevent amyloid beta proteins from clumping in human nerve cells. The most successful extract was from the Tettnang hop, found in many types of lagers and lighter ales. When that extract was separated into fractions, the one containing a high level of polyphenols showed the most potent antibiotic and aggregation-inhibiting activity. It also promoted processes that allow the body to clear out misfolded, neurotoxic proteins. Finally, the team tested the Tettnang extract in a C. elegans model and found that it protected the worms from AD-related paralysis, though the effect was not very pronounced. The researchers say that although this work may not justify drinking more bitter brews, it shows that hop compounds could serve as the basis for nutraceuticals that combat the development of AD.

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Brain discovery holds key to boosting body's ability to fight Alzheimer's, MS

UVA Health researchers have discovered a molecule in the brain responsible for orchestrating the immune system's responses to Alzheimer's disease and multiple sclerosis (MS), potentially allowing doctors to supercharge the body's ability to fight those and other devastating neurological diseases.

The molecule the researchers identified, called a kinase, is crucial to both removing plaque buildup associated with Alzheimer's and preventing the debris buildup that causes MS, the researchers found. It does this, the researchers showed, by directing the activity of brain cleaners called microglia. These immune cells were once largely ignored by scientists but have, in recent years, proved vital players in brain health.

UVA's important new findings could one day let doctors augment the activity of microglia to treat or protect patients from Alzheimer's, MS and other neurodegenerative diseases, the researchers report.

"Unfortunately, medical doctors do not currently possess effective treatments to target the root causes of most neurodegenerative diseases, such as Alzheimer's, Parkinson's or ALS [amyotrophic lateral sclerosis, commonly called Lou Gehrig's disease]. In our studies, we have discovered a master controller of the cell type and processes that are required to protect the brain from these disorders," said senior researcher John Lukens, PhD, of the University of Virginia School of Medicine and its Center for Brain Immunology and Glia (BIG), as well as the Carter Immunology Center and the UVA Brain Institute. "Our work further shows that targeting this novel pathway provides a potent strategy to eliminate the toxic culprits that cause memory loss and impaired motor control in neurodegenerative disease."

Toxic Brain Buildup

Many neurodegenerative diseases, including Alzheimer's and MS, are thought to be caused by the brain's inability to cleanse itself of toxic buildup. Recent advances in neuroscience research have shed light on the importance of microglia in removing harmful debris from the brain, but UVA's new discovery offers practical insights into how this cleaning process occurs -- and the dire consequences when it doesn't.

Using a mouse model of Alzheimer's disease, the UVA researchers found that a lack of the molecule they identified, spleen tyrosine kinase, triggered plaque buildup in the brain and caused the mice to suffer memory loss -- like the symptoms seen in humans with Alzheimer's. Further, the neuroscientists were able to reduce the plaque buildup by activating this molecule and microglia in the brain, suggesting a potential treatment approach for human patients, though that would require significantly more research and testing.

"Our work has described a critical element of microglial function during Alzheimer's disease and MS," said researcher Hannah Ennerfelt, the first author of a new scientific paper outlining the findings. "Understanding the underlying biology of these cells during neurodegeneration may allow for scientists and doctors to develop increasingly informed and effective therapeutic interventions."

A lack of the molecule in a mouse model of MS, meanwhile, led to the buildup of damaged myelin, a protective coating on nerve cells. When myelin is damaged, the cells cannot transmit messages properly, causing MS symptoms such as mobility problems and muscle spasms. The UVA researchers conclude in a new scientific paper that the molecule they identified, abbreviated as SYK, is "critically involved" in the crucial removal of myelin debris. "If boosting SYK activity in microglia can decrease the amount of myelin debris in MS lesions, developing new drugs to target SYK could stop the progression of MS and help to reverse the damage," said Elizabeth L. Frost, PhD, a critical researcher on the project. "This is an especially promising option given that most of the currently available drugs for MS treatment dampen adaptive immunity. These immunosuppressive drugs lead to susceptibility to infection and higher risk of potentially fatal side effects like progressive multifocal leukoencephalopathy. Additionally, some forms of MS do not have a strong involvement of the immune system, and therefore there are currently very limited treatment options for those patients."

"Targeting SYK in microglia," she noted, "would circumvent multiple limitations of present-day therapeutics for MS."

Based on their promising results, the researchers report that targeting the molecule to stimulate the brain's immune activity could offer a way to treat not just Alzheimer's and MS but a "spectrum" of neurodegenerative diseases.

"These findings are especially exciting because they point to a treatment avenue in which we could alter the behavior of these native brain cells, microglia, to behave in a more neuroprotective way," said researcher Coco Holliday, a UVA undergraduate working in the Lukens lab. "It could potentially be applied to a variety of different neurological diseases that all share the problem of a buildup of toxic waste in the brain. It's been a very exciting project to be a part of."

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How a single protein could unlock age-related vision loss

Research led by Sanford Burnham Prebys professor Francesca Marassi, Ph.D., is helping to reveal the molecular secrets of macular degeneration, which causes almost 90% of all age-related vision loss. The study, published recently in the Biophysical Journal, describes the flexible structure of a key blood protein involved in macular degeneration and other age-related diseases, such as Alzheimer's and atherosclerosis.

"Proteins in the blood are under constant and changing pressure because of the different ways blood flows throughout the body," says Marassi. "For example, blood flows more slowly through small blood vessels in the eyes compared to larger arteries around the heart. Blood proteins need to be able to respond to these changes, and this study gives us fundamental truths about how they adapt to their environment, which is critical to targeting those proteins for future treatments."

There are hundreds of proteins in our blood, but the researchers focused on vitronectin, one of the most abundant. In addition to circulating in high concentrations in the blood, vitronectin is found in the scaffolding between cells and is also an important component of cholesterol.

Vitronectin is a key player in many age-related diseases, but for Marassi's team, the most promising target is macular degeneration, which affects as many as 11 million people in the United States. This number is expected to double by 2050.

"This protein is an important target for macular degeneration because it accumulates in the back of the eye, causing vision loss. Similar deposits appear in the brain in Alzheimer's disease and in the arteries in atherosclerosis," says Marassi. "We want to understand why this happens and leverage this knowledge to develop new treatments."

To approach this question, the researchers were interested in learning how the protein changes its structure at different temperatures and under different levels of pressure, approximating what happens in the human body.

"Determining the structure of a protein is the most important part of determining its function," adds Marassi. Through detailed biochemical analysis, the researchers found that the protein can subtly change its shape under pressure. These changes cause it to bond more easily to calcium ions in the blood, which the researchers suggest leads to the buildup of calcified plaque deposits characteristic of macular degeneration and other age-related diseases.

"It's a very subtle rearrangement of the molecular structure, but it has a big impact on how the protein functions," says Marassi. "The more we learn about the protein on a structural and mechanistic level, the better chance we have of successfully targeting it with treatments."

These structural insights will streamline the development of treatments for macular degeneration because it will allow researchers and their partners in the biotech industry to custom-design antibodies that selectively block the protein's calcium binding without disrupting its other important functions in the body.

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Long term high-fat diet expands waistline and shrinks brain

New research shows that fatty foods may not only be adding to your waistline but also playing havoc with your brain.

An international study led by UniSA neuroscientists Professor Xin-Fu Zhou and Associate Professor Larisa Bobrovskaya has established a clear link between mice fed a high-fat diet for 30 weeks, resulting in diabetes, and a subsequent deterioration in their cognitive abilities, including developing anxiety, depression and worsening Alzheimer's disease.

Mice with impaired cognitive function were also more likely to gain excessive weight due to poor metabolism caused by brain changes.

Researchers from Australia and China have published their findings in Metabolic Brain Disease.

UniSA neuroscientist and biochemist Associate Professor Larisa Bobrovskaya says the research adds to the growing body of evidence linking chronic obesity and diabetes with Alzheimer's disease, predicted to reach 100 million cases by 2050.

"Obesity and diabetes impair the central nervous system, exacerbating psychiatric disorders and cognitive decline. We demonstrated this in our study with mice," Assoc Prof Bobrovskaya says.

In the study, mice were randomly allocated to a standard diet or a high-fat diet for 30 weeks, starting at eight weeks of age. Food intake, body weight and glucose levels were monitored at different intervals, along with glucose and insulin tolerance tests and cognitive dysfunction.

The mice on the high-fat diet gained a lot of weight, developed insulin resistance and started behaving abnormally compared to those fed a standard diet.

Genetically modified Alzheimer's disease mice showed a significant deterioration of cognition and pathological changes in the brain while fed the high fat diet.

"Obese individuals have about a 55 per cent increased risk of developing depression, and diabetes will double that risk," Assoc Prof Bobrovskaya says.

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In the race to solve Alzheimer's disease, scientists find more needles in the haystack

21 million. That's the number of genetic variations in the human genome that researchers are sifting to identify patterns predisposing people to Alzheimer's disease.

It's a huge haystack, and Alzheimer's-related genetic variations, like needles, are miniscule in comparison. Sudha Seshadri, MD, and other faculty at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) readily attest to the deep gulf between what is known about Alzheimer's genetics and what is yet to be discovered.

Dr. Seshadri, Habil Zare, PhD, and colleagues at the university's Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases are investigators on a global project to answer the many Alzheimer's riddles. Dr. Seshadri is a founding principal investigator of the International Genomics of Alzheimer's Project, commonly called IGAP. Glenn Biggs Institute faculty contributed data for the newest research from IGAP, published April 4 in Nature Genetics, and helped craft the discussion on implications of the findings, Dr. Seshadri said.

Large sample

Genomic data of half a million people were used in this latest IGAP study, including 30,000 people with confirmed Alzheimer's disease and 47,000 people categorized as proxies. Researchers could not be sure that proxy participants had Alzheimer's clinically, but they were included based on conversations with their children.

"In Alzheimer's disease research you need many samples, because some of these variants are very rare, and if you want to detect them, you need to study many, many people," said Dr. Zare, assistant professor of cell systems and anatomy in the Joe R. and Teresa Lozano Long School of Medicine and an expert in computational biology and bioinformatics. "The only way to get there is through collaboration between centers and consortia, and IGAP was established for such kind of collaboration."

IGAP conducts genome-wide association studies. These studies reveal areas of the genome, the encyclopedia of human genes, that vary between people who have Alzheimer's disease and people who don't.

"We are looking for the genetic basis so as to better understand all the different types of biology that may be responsible for Alzheimer's disease," said Dr. Seshadri, founding director of the Biggs Institute and professor of neurology in the Long School of Medicine. "As we include data from more and more people, we are able to find variants that are fairly rare, that are only seen in about 1% of the population."

Sea change

In 2009, the year of the first genome-wide association studies, researchers knew of one gene, called APOE, associated with late-onset Alzheimer's disease. Before the April 4 journal publication, researchers had a list of 40 such genes. The new paper confirmed 33 of them in a larger population sample and added 42 new genetic variants not described before.

"We've doubled the number of genes that we know are associated with Alzheimer's disease," Dr. Seshadri said. "Each of these genetic variants is a route to understanding the biology and a potential target for treatment."

Emerging pathways of Alzheimer's biology suggest the involvement of inflammation, cell senescence, central nervous system cells called microglia, and many others. Finding genetic variations will shed light on these pathways.

"A certain percentage of them are what are called druggable targets," Dr. Zare said. "Some are considered more likely to yield drugs."

Diversity needed

The study published in Nature Genetics is confined to certain people groups, which makes it impossible to generalize the gene variations worldwide.

One of the challenges with this paper, as well, is it is largely in persons of European ancestry," Dr. Seshadri said. "So, we hope to bring, over the next few years, a much larger sample of Hispanic and other minority populations to further improve gene discovery."

The South Texas Alzheimer's Disease Research Center (ADRC), a collaboration of the Glenn Biggs Institute, UT Health San Antonio and The University of Texas Rio Grande Valley, is on a mission to bring the region's sizable Hispanic population into genetic studies and other initiatives such as clinical trials. ADRCs are National Institute on Aging Centers of Excellence.

Older Hispanic adults are estimated to be at 1.5 times greater risk of Alzheimer's and other dementias than non-Hispanic whites. Dementia is costing individuals, caregivers, families and the nation an estimated $321 billion in 2022, according to the Alzheimer's Association.

"Our South Texas ADRC is here to treat people and make discoveries that lead to better treatments," Dr. Seshadri said.

The needles in the haystack are being located, and this is having results.

"We are part of this international team and are finding a lot of needles in this huge haystack of 21 million variants," Dr. Zare said.

Partners are crucial

Dr. Seshadri said a gene called SP1 is being considered for drug development by industry. SP1 was identified in an earlier study conducted by IGAP.

"That was a clue discovered years ago and now we have more clues, and hopefully we will have more promising targets in the near future," Dr. Zare said.

As the quest to end the suffering endured by individuals and families continues, the researchers acknowledge the partners who play significant roles.

"We would like to thank each of the collaborators within IGAP, and all the patients and families that join such studies, and the National Institute on Aging, which is our funder," Dr. Seshadri said.

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Extended napping in seniors may signal dementia

Daytime napping among older people is a normal part of aging -- but it may also foreshadow Alzheimer's disease and other dementias. And once dementia or its usual precursor, mild cognitive impairment, are diagnosed, the frequency and/or duration of napping accelerates rapidly, according to a new study.

The study, led by UC San Francisco and Harvard Medical School together with Brigham and Women's Hospital, its teaching affiliate, departs from the theory that daytime napping in older people serves merely to compensate for poor nighttime sleep. Instead, it points to work by other UCSF researchers suggesting that dementia may affect the wake-promoting neurons in key areas of the brain, the researchers state in their paper publishing March 17, 2022, in Alzheimer's and Dementia: The Journal of the Alzheimer's Association.

"We found the association between excessive daytime napping and dementia remained after adjusting for nighttime quantity and quality of sleep," said co-senior author Yue Leng, MD, PhD, of the UCSF Department of Psychiatry and Behavioral Sciences.

"This suggested that the role of daytime napping is important itself and is independent of nighttime sleep," said Leng, who partnered with Kun Hu, PhD, of Harvard Medical School, in senior-authoring the paper.

Watch-Like Devices, Annual Evaluations Used to Measure Naps, Cognition

In the study, the researchers tracked data from 1,401 seniors, who had been followed for up to 14 years by the Rush Memory and Aging Project at the Rush Alzheimer's Disease Center in Chicago. The participants, whose average age was 81 and of whom approximately three-quarters were female, wore a watch-like device that tracked mobility. Each prolonged period of non-activity from 9 a.m. to 7 p.m. was interpreted as a nap.

The device was worn every year continuously for up to 14 days, and once a year each participant underwent a battery of neuropsychological tests to evaluate cognition. At the start of the study 75.7% of participants had no cognitive impairment, while 19.5% had mild cognitive impairment and 4.1% had Alzheimer's disease.

For participants who did not develop cognitive impairment, daily daytime napping increased by an average 11 minutes per year. The rate of increase doubled after a diagnosis of mild cognitive impairment to a total of 24 minutes and nearly tripled to a total of 68 minutes after a diagnosis of Alzheimer's disease.

When the researchers looked at the 24% of participants who had normal cognition at the start of the study but developed Alzheimer's six years later, and compared them with those whose cognition remained stable, they found differences in napping habits. Participants who napped more than an hour a day had a 40% higher risk of developing Alzheimer's than those who napped less than an hour a day; and participants who napped at least once a day had a 40% higher risk of developing Alzheimer's than those who napped less than once a day.

The research confirms the results of a 2019 study, of which Leng was the first author, that found older men who napped two hours a day had higher odds of developing cognitive impairment that those who napped less than 30 minutes a day. The current study builds on these findings by evaluating both daytime napping and cognition each year, hence addressing directionality, Leng notes.

Loss of Wake-Promoting Neurons May Account for Longer Naps

According to the researchers, increase in napping may be explained by a further 2019 study, by other UCSF researchers, comparing the postmortem brains of people with Alzheimer's disease to those without cognitive impairment. Those with Alzheimer's disease were found to have fewer wake-promoting neurons in three brain regions. These neuronal changes appear to be linked to tau tangles -- a hallmark of Alzheimer's, characterized by increased activity of enzymes causing the protein to misfold and clump.

"It is plausible that our observed associations of excessive daytime napping at baseline, and increased risk for Alzheimer's disease during follow-up, may reflect the effect of Alzheimer's disease pathology at preclinical stages," the authors noted.

The study shows for the first time that napping and Alzheimer's disease "seem to be driving each other's changes in a bi-directional way," said Leng, who is also affiliated with the UCSF Weill Institute for Neurosciences. "I don't think we have enough evidence to draw conclusions about a causal relationship, that it's the napping itself that caused cognitive aging, but excessive daytime napping might be a signal of accelerated aging or cognitive aging process," she said.

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How does the brain make memories?

Researchers have discovered two types of brain cells that play a key role in dividing continuous human experience into distinct segments that can be recalled later. The discovery provides new promise as a path toward development of novel treatments for memory disorders such as dementia and Alzheimer's disease.

In a study led by Cedars-Sinai, researchers have discovered two types of brain cells that play a key role in dividing continuous human experience into distinct segments that can be recalled later. The discovery provides new promise as a path toward development of novel treatments for memory disorders such as dementia and Alzheimer's disease.

The study, part of a multi-institutional BRAIN Initiative consortium funded by the National Institutes of Health and led by Cedars-Sinai, was published in the peer-reviewed journal Nature Neuroscience. As part of ongoing research into how memory works, Ueli Rutishauser, PhD, professor of Neurosurgery, Neurology, and Biomedical Sciences at Cedars-Sinai, and co-investigators looked at how brain cells react as memories are formed.

"One of the reasons we can't offer significant help for somebody who suffers from a memory disorder is that we don't know enough about how the memory system works," said Rutishauser, senior author of the study, adding that memory is foundational to us as human beings.

Human experience is continuous, but psychologists believe, based on observations of people's behavior, that memories are divided by the brain into distinct events, a concept known as event segmentation. Working with 19 patients with drug-resistant epilepsy, Rutishauser and his team were able to study how neurons perform during this process.

Patients participating in the study had electrodes surgically inserted into their brains to help locate the focus of their epileptic seizures, allowing investigators to record the activity of individual neurons while the patients viewed film clips that included cognitive boundaries.

While these boundaries in daily life are nuanced, for research purposes, the investigators focused on "hard" and "soft" boundaries.

"An example of a soft boundary would be a scene with two people walking down a hallway and talking, and in the next scene, a third person joins them, but it is still part of the same overall narrative," said Rutishauser, interim director of the Center for Neural Science and Medicine and the Board of Governors Chair in Neurosciences at Cedars-Sinai.

In the case of a hard boundary, the second scene might involve a completely different set of people riding in a car. "The difference between hard and soft boundaries is in the size of the deviation from the ongoing narrative," Rutishauser said. "Is it a totally different story, or like a new scene from the same story?"

When study participants watched film clips, investigators noted that certain neurons in the brain, which they labeled "boundary cells," increased their activity after both hard and soft boundaries. Another group of neurons, labeled "event cells," increased their activity only in response to hard boundaries, but not soft boundaries.

Rutishauser and his co-investigators theorize that peaks in the activity of boundary and event cells -- which are highest after hard boundaries, when both types of cells fire -- send the brain into the proper state for initiating a new memory.

"A boundary response is kind of like creating a new folder on your computer," said Rutishauser. "You can then deposit files in there. And when another boundary comes around, you close the first folder and create another one."

To retrieve memories, the brain uses boundary peaks as what Rutishauser calls "anchors for mental time travel."

"When you try to remember something, it causes brain cells to fire," Rutishauser said. "The memory system then compares this pattern of activity to all the previous firing peaks that happened shortly after boundaries. If it finds one that is similar, it opens that folder. You go back for a few seconds to that point in time, and things that happened then come into focus."

To test their theory, investigators gave study participants two memory tests.

They first showed participants a series of still images and asked them whether or not they had seen them in the film clips they had viewed. Study participants were more likely to remember images that closely followed a hard or soft boundary, when a new "memory folder" would have been created.

Investigators also showed participants pairs of images from film clips they had viewed and asked which of the images appeared first. Participants had difficulty remembering the correct order of images that appeared on opposite sides of a hard boundary, possibly because the brain had segmented those images into separate memory folders.

Rutishauser said that therapies that improve event segmentation could help patients with memory disorders. Even something as simple as a change in atmosphere can amplify event boundaries, he explained.

"The effect of context is actually quite strong," Rutishauser said. "If you study in a new place, where you have never been before, instead of on your couch where everything is familiar, you will create a much stronger memory of the material."

The research team included postdoctoral fellow Jie Zheng, PhD, and neuroscientist Gabriel Kreiman, PhD, from Boston Children's Hospital; neurosurgeon Taufik A. Valiante, MD, PhD, of the University of Toronto; and Adam Mamelak, MD, professor of Neurosurgery and director of the Functional Neurosurgery Program at Cedars-Sinai.

In follow-up studies, the team plans to test the theory that boundary and event cells activate dopamine neurons when they fire, and that dopamine, a chemical that sends messages between cells, might be used as a therapy to strengthen memory formation.

Rutishauser and his team also noted during this study that when event cells fired in time with one of the brain's internal rhythms, the theta rhythm -- a repetitive pattern of activity linked to learning, memory and navigation -- subjects were better able to remember the order of images they had seen. This is an important new insight because it shows that deep brain stimulation that adjusts theta rhythms could prove therapeutic for memory disorders.

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'Supermeres' may carry clues to cancer, Alzheimer's disease and COVID-19

Researchers at Vanderbilt University Medical Center have discovered a nanoparticle released from cells, called a "supermere," which contains enzymes, proteins and RNA associated with multiple cancers, cardiovascular disease, Alzheimer's disease and even COVID-19.

The discovery, reported in Nature Cell Biology, is a significant advance in understanding the role extracellular vesicles and nanoparticles play in shuttling important chemical "messages" between cells, both in health and disease.

"We've identified a number of biomarkers and therapeutic targets in cancer and potentially in a number of other disease states that are cargo in these supermeres," said the paper's senior author, Robert Coffey, MD. "What is left to do now is to figure out how these things get released."

Coffey, the Ingram Professor of Cancer Research and professor of Medicine and Cell & Developmental Biology, is internationally known for his studies of colorectal cancer. His team is currently exploring whether the detection and targeting of cancer-specific nanoparticles in the bloodstream could lead to earlier diagnoses and more effective treatment.

In 2019 Dennis Jeppesen, PhD, a former research fellow in Coffey's lab who is now a research instructor in Medicine, used advanced techniques to isolate and analyze small membrane-enclosed extracellular vesicles called "exosomes."

That year, using high-speed ultracentrifugation, another of Coffey's colleagues, Qin Zhang, PhD, research assistant professor of Medicine, devised a simple method to isolate a nanoparticle called an "exomere" that lacks a surface coat.

In the current study, Zhang took the "supernatant," or fluid that remains after the exomeres have been spun into a "pellet," and spun the fluid faster and longer.

The result was a pellet of nanoparticles isolated from the supernatant of the exomere spin -- which the researchers named supermeres. "They're also super-interesting," Coffey quipped, "because they contain many cargo previously thought to be in exosomes."

For one thing, supermeres carry most of the extracellular RNA released by cells and which is found in the bloodstream. Among other functional properties, cancer-derived supermeres can "transfer" drug resistance to tumor cells, perhaps via the RNA cargo they deliver, the researchers reported.

Supermeres are important carriers of TGFBI, a protein that in established tumors promotes tumor progression. TGFBI thus may be a useful marker in liquid biopsies for patients with colorectal cancer, the researchers noted.

They also carry ACE2, a cell-surface receptor that plays a role in cardiovascular disease and is the target of the COVID-19 virus. This raises the possibility that ACE2 carried by supermeres could serve as a "decoy" to bind the virus and prevent infection.

Another potentially important cargo is APP, the amyloid-beta precursor protein implicated in the development of Alzheimer's disease. Supermeres can cross the blood-brain barrier, suggesting that their analysis could improve early diagnosis or possibly even targeted treatment of the disease.

"The identification of this rich plethora of bioactive molecules … raises interesting questions about the function of supermeres, and heightens interest in the potential of these particles as biomarkers for diseases," researchers at the University of Notre Dame noted in a review published with the paper.

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Hit the sleep ‘sweet spot’ to keep brain sharp

Like so many other good things in life, sleep is best in moderation. A multiyear study of older adults found that both short and long sleepers experienced greater cognitive decline than people who slept a moderate amount, even when the effects of early Alzheimer's disease were taken into account. The study was led by researchers at Washington University School of Medicine in St. Louis.

Poor sleep and Alzheimer's disease are both associated with cognitive decline, and separating out the effects of each has proven challenging. By tracking cognitive function in a large group of older adults over several years and analyzing it against levels of Alzheimer's-related proteins and measures of brain activity during sleep, the researchers generated crucial data that help untangle the complicated relationship among sleep, Alzheimer's and cognitive function. The findings could aid efforts to help keep people's minds sharp as they age.

The findings are published Oct. 20 in the journal Brain.

"It's been challenging to determine how sleep and different stages of Alzheimer's disease are related, but that's what you need to know to start designing interventions," said first author Brendan Lucey, MD, an associate professor of neurology and director of the Washington University Sleep Medicine Center. "Our study suggests that there is a middle range, or 'sweet spot,' for total sleep time where cognitive performance was stable over time. Short and long sleep times were associated with worse cognitive performance, perhaps due to insufficient sleep or poor sleep quality. An unanswered question is if we can intervene to improve sleep, such as increasing sleep time for short sleepers by an hour or so, would that have a positive effect on their cognitive performance so they no longer decline? We need more longitudinal data to answer this question."

Alzheimer's is the main cause of cognitive decline in older adults, contributing to about 70% of dementia cases. Poor sleep is a common symptom of the disease and a driving force that can accelerate the disease's progression. Studies have shown that self-reported short and long sleepers are both more likely to perform poorly on cognitive tests, but such sleep studies typically do not include assessments of Alzheimer's disease.

To tease apart the separate effects of sleep and Alzheimer's disease on cognition, Lucey and colleagues turned to volunteers who participate in Alzheimer's studies through the university's Charles F. and Joanne Knight Alzheimer Disease Research Center. Such volunteers undergo annual clinical and cognitive assessments, and provide a blood sample to be tested for the high-risk Alzheimer's genetic variant APOE4. For this study, the participants also provided samples of cerebrospinal fluid to measure levels of Alzheimer's proteins, and each slept with a tiny electroencephalogram (EEG) monitor strapped to their foreheads for four to six nights to measure brain activity during sleep.

In total, the researchers obtained sleep and Alzheimer's data on 100 participants whose cognitive function had been monitored for an average of 4 1/2 years. Most (88) had no cognitive impairments, 11 were very mildly impaired, and one had mild cognitive impairment. The average age was 75 at the time of the sleep study.

The researchers found a U-shaped relationship between sleep and cognitive decline. Overall, cognitive scores declined for the groups that slept less than 4.5 or more than 6.5 hours per night -- as measured by EEG -- while scores stayed stable for those in the middle of the range. EEG tends to yield estimates of sleep time that are about an hour shorter than self-reported sleep time, so the findings correspond to 5.5 to 7.5 hours of self-reported sleep, Lucey said.

The U-shaped relationship held true for measures of specific sleep phases, including rapid-eye movement (REM), or dreaming, sleep; and non-REM sleep. Moreover, the relationship held even after adjusting for factors that can affect both sleep and cognition, such as age, sex, levels of Alzheimer's proteins, and the presence of APOE4.

"It was particularly interesting to see that not only those with short amounts of sleep but also those with long amounts of sleep had more cognitive decline," said co-senior author David Holtzman, MD, a professor of neurology. "It suggests that sleep quality may be key, as opposed to simply total sleep."

Each person's sleep needs are unique, and people who wake up feeling rested on short or long sleep schedules should not feel compelled to change their habits, Lucey said. But those who are not sleeping well should be aware that sleep problems often can be treated.

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Researchers find warning signs for dementia in the blood

Researchers at the DZNE and the University Medical Center Göttingen (UMG) have identified molecules in the blood that can indicate impending dementia. Their findings, which are presented in the scientific journal EMBO Molecular Medicine, are based on human studies and laboratory experiments. Various university hospitals across Germany were also involved in the investigations. The biomarker described by the team led by Prof. André Fischer is based on measuring levels of so-called microRNAs. The technique is not yet suitable for practical use; the scientists therefore aim to develop a simple blood test that can be applied in routine medical care to assess dementia risk. According to the study data, microRNAs could potentially also be targets for dementia therapy.

"When symptoms of dementia manifest, the brain has already been massively damaged. Presently, diagnosis happens far too late to even have a chance for effective treatment. If dementia is detected early, the odds of positively influencing the course of the disease increase," says André Fischer, research group leader and spokesperson at the DZNE site in Göttingen and professor at the Department of Psychiatry and Psychotherapy at UMG. "We need tests that ideally respond before the onset of dementia and reliably estimate the risk of later disease. In other words, tests that give an early warning. We are confident that our current study results pave the way for such tests."

Molecular Signature

The biomarker that Fischer and his colleagues have found is based on measuring so-called microRNAs in the blood. MicroRNAs are molecules with regulatory properties: they influence the production of proteins and thus a key process in the metabolism of every living being. "There are many different microRNAs and each of them can regulate entire networks of interdependent proteins and thus influence complex processes in the organism. So, microRNAs have a broad impact. We wanted to find out whether there are specific microRNAs whose presence in the blood correlates with mental fitness," Fischer says.

Through extensive studies in humans, mice and cell cultures, the researchers ultimately identified three microRNAs whose levels were associated with mental performance. For this, they analyzed data from both young, cognitively normal individuals and from elderly people with mild cognitive impairment (MCI). For the data from healthy individuals, the Göttingen scientists cooperated with Munich University Hospital. The data from MCI patients came from a DZNE study that has been running for years and involves university clinics throughout Germany.

Omens of Dementia

In the end, the various findings came together like pieces of a puzzle: In healthy individuals, levels of microRNAs correlated with mental fitness. The lower the blood level, the better the subjects performed in cognition tests. In mice, in turn, this score increased even before the rodents started to show mental decline -- regardless of whether this was due to age or because they developed symptoms similar to those of Alzheimer's dementia. Further evidence came from patients with MCI: Of those in whom the blood marker was highly elevated, about 90 percent developed Alzheimer's disease within two years. "We therefore see an increased blood level of these three microRNAs as a harbinger of dementia," Fischer says. "We estimate that in humans this biomarker indicates a development that is about two to five years in the future."

Potential Targets for Therapy

In their studies on mice and cell cultures, the researchers also found that the three identified microRNAs influence inflammatory processes in the brain and "neuroplasticity" which includes the ability of neurons to establish connections with each other. This suggests that the three microRNAs are more than warning signals. "In our view, they are not only markers, but also have an active impact on pathological processes. This makes them potential targets for therapy," Fischer says. "Indeed, we see in mice that learning ability improves when these microRNAs are blocked with drugs. We've observed this in mice with age-related mental deficits, as well as in mice with brain damage similar to that occurring in Alzheimer's disease."

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A 'cousin' of Viagra reduces obesity by stimulating cells to burn fat

Researchers at Johns Hopkins Medicine have found that a drug first developed to treat Alzheimer's disease, schizophrenia and sickle cell disease reduces obesity and fatty liver in mice and improves their heart function -- without changes in food intake or daily activity.

These findings, published online Oct. 7 in the Journal of Clinical Investigation, reveal that a chemical inhibitor of the enzyme PDE9 stimulates cells to burn more fat. This occurred in male mice and in female mice whose sex hormones were reduced by removing their ovaries, thus mimicking menopause. Postmenopausal women are well known to be at increased risk for obesity around their waist as well as at risk for cardiovascular and metabolic disease.

Inhibiting PDE9 did not cause these changes in female mice that had their ovaries, so female sex hormone status was important in the study.

"Currently, there isn't a pill that has been proven effective for treating severe obesity, yet such obesity is a global health problem that increases the risk of many other diseases," says senior investigator David Kass, M.D., Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine. "What makes our findings exciting is that we found an oral medication that activates fat-burning in mice to reduce obesity and fat buildup in organs like the liver and heart that contribute to disease; this is new."

This study follows work reported by the same laboratory in 2015 that first showed the PDE9 enzyme is present in the heart and contributes to heart disease triggered by high blood pressure. Blocking PDE9 increases the amount of a small molecule known as cyclic GMP, which in turn controls many aspects of cell function throughout the body. PDE9 is the enzyme cousin of another protein called PDE5, which also controls cyclic GMP and is blocked by drugs such as Viagra. Inhibitors of PDE9 are experimental, so there is no drug name yet.

Based on these results, the investigators suspected PDE9 inhibition might improve cardiometabolic syndrome (CMS), a constellation of common conditions including high blood pressure; high blood sugar, cholesterol and triglycerides; and excess body fat, particularly around the waist. CMS is considered a pandemic by medical experts and a major risk factor for heart disease, stroke, type 2 diabetes, cancers and COVID-19.

While PDE9 inhibitors remain experimental, they have been developed by several pharmaceutical companies and tested in humans for diseases such as Alzheimer's and sickle cell. The current mouse study used a PDE9 inhibitor made by Pfizer Inc. (PF-04447943) that was first tested for Alzheimer's disease, though eventually abandoned for this use. Between the two reported clinical trials, over 100 subjects received this drug, and it was found to be well tolerated with no serious adverse side effects. A different PDE9 inhibitor is now being tested for human heart failure.

To test the effects of a PDE9 inhibitor on obesity and cardiometabolic syndrome, the researchers put mice on a high-fat diet that led to doubling their body weight, high blood lipids and diabetes after four months. A group of female mice had their ovaries surgically removed, and most of the mice also had a pressure stress applied to the heart to better mimic cardiometabolic syndrome. The mice were then assigned to receive either the PDE9 inhibitor or a placebo by mouth over the next six to eight weeks.

In female mice without their ovaries (a model of postmenopause), the difference in median percent weight change between the drug and placebo groups was -27.5%, and in males it was -19.5%. Lean body mass was not altered in either group, nor was daily food consumption or physical activity. The PDE9 inhibitor lowered blood cholesterol and triglycerides, and reduced fat in the liver to levels found in mice fed a normal diet. The heart also improved with PDE9 inhibition, with ejection fraction (which measures the percentage of blood leaving the heart each time it contracts) relatively higher by 7%-15% and heart mass (hypertrophy) rising 70% less compared with the placebo. An increase in heart mass is evidence of abnormal heart stress. However, having this lowered by the inhibitor indicates stress on the heart was reduced.

The investigators found PDE9 inhibition produces these effects by activating a master regulator of fat metabolism known as PPARa. By stimulating PPARa, levels of genes for proteins that control fat uptake into cells and their use as fuel are broadly increased. When PPARa was blocked in cells or the whole animal, the effects from PDE9 inhibition on obesity and fat-burning were also lost. They found estrogen normally plays this role of PPARa on fat regulation in females, but when its levels fall like they do after menopause, PPARa becomes more important to regulate fat and so PDE9 inhibition has a greater effect.

"The finding that the experimental drug did not benefit female mice that had their ovaries shows that these sex hormones, particularly estrogen, had already achieved what inhibiting PDE9 does to stimulate fat-burning," notes Sumita Mishra, the research associate who performed much of the work. "Menopause reduces sex hormone levels, and their control over fat metabolism then shifts to the protein regulated by PDE9, so the drug treatment is now effective."

According to the U.S. Centers for Disease Control and Prevention, more than 40% of people living in the U.S. are obese; and 43% of American women over the age of 60 -- long past menopause -- are considered obese.

Kass notes that if his lab's findings in mice apply to people, someone weighing 250 pounds could lose about 50 pounds with an oral PDE9 inhibitor without changing eating or exercise habits.

"I'm not suggesting to be a couch potato and take a pill, but I suspect that combined with diet and exercise, the effects from PDE9 inhibition may be even greater," says Kass. The next step would be testing in humans to see if PDE9 inhibitors produce similar effects in men and postmenopausal women.

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Scientists discover early signs of frontotemporal dementia in personalized cerebral organoids

Frontotemporal dementias are a group of fatal and debilitating brain disorders for which there are no cures. In an article published July 26 in Cell, Mount Sinai researchers describe how they were able to recreate much of the damage seen in a widely studied form of the disease by growing special types of cerebral organoids in petri dishes. This form of the disease is caused by a genetic mutation in tau, a protein that is a hallmark of Alzheimer's disease and other dementias. By studying these organoids, the scientists discovered how the mutated tau protein may trigger the death of a specific class of neurons known to be vulnerable in frontotemporal dementia. They also showed that they could prevent the death of these neurons by treating the organoids with an experimental drug, originally designed to combat Crohn's disease.

"Frontotemporal dementia is a devastating disease for patients and their loved ones. Understanding the causes of dementia can be difficult, as most of the damage to the brain occurs well before any symptoms appear. It's like trying to unravel the events that created a crime scene. In this study, we were able to model many aspects of the pathology seen in the brains of patients who carry the V337M mutation in tau," said Alison M. Goate, DPhil, Director, Ronald M. Loeb Center for Alzheimer's Disease at Mount Sinai, and a senior author of the study. "Our results identified several very early transcriptomic and proteomic changes that lead to the formation of tau pathology and neuronal death. Our goal is to help researchers develop novel treatments against frontotemporal dementias and prevent the suffering experienced by patients and their families."

Frontotemporal dementia is a rare form of dementia that usually begins between ages 40 and 60. It affects the front and side (temporal) areas of the brain, leading to behavior changes and difficulty with speaking and thinking.

The study was led by Kathryn Bowles, PhD, an instructor in Dr. Goate's lab at Mount Sinai. Working with scientists at the Neural Stem Cell Institute (NSCI) in Rensselaer, New York, Washington University in St. Louis, Missouri, Massachusetts General Hospital in Boston, and the University of Southern California, Los Angeles, the researchers created thousands of cerebral organoids from induced pluripotent stem cells (iPSCs).

Induced pluripotent stem cells are created by genetically and chemically reprogramming a person's skin or blood cells into newborn stem cells, which have the potential to become any cell in the body. From these stem cells, the NSCI created thousands of tiny, 3D cerebral organoids, which mimic the early growth and development of the cerebral cortex for intensive study by collaborating scientific groups.

"Induced pluripotent stem cells are powerful tools. They allow researchers to study each patient's personalized disease in a petri dish," said Sally Temple, PhD, Scientific Director of the NSCI and a senior author of the study. "In this study we were able to take this idea to the next level. By combining iPSC-organoid technology with high-throughput, single cell gene activity analysis, we were able to get a better look at what might be going on in a patient's brain at early stages of disease development, even before symptoms emerge."

In this study, the researchers examined the growth and development of organoids derived from the stem cells of three patients, all of whom carried the V337M mutation in tau. They then compared their results with those observed in "isogenic," control organoids. The controls were derived from patient stem cells in which the disease-causing mutation was genetically corrected.

After six months of growth, signs of neurodegeneration were seen in the organoids. Most notably, the patient-derived organoids had fewer excitatory neurons than those derived from the control cells, demonstrating that the tau mutation was sufficient to cause higher levels of cell death of this specific class of neurons. Excitatory neurons usually fire in response to the neurochemical glutamate and are known to die at abnormally high levels in frontotemporal dementia. The patient-derived organoids also had higher levels of harmful versions of tau protein and elevated levels of inflammation.

"Excitatory neuron cell death, tau protein deposits, and inflammation are classic hallmarks of the kind of damage seen in many forms of frontotemporal dementia," said Dr. Bowles. "What we wanted to know next was: what are the cellular and molecular processes that occur before the appearance of these disease hallmarks?"

The researchers found clues by examining two- and four-month-old organoids.

For instance, two-month-old mutant organoids appeared to be undergoing elevated levels of cellular stress, whereas four-month-old ones developed problems with autophagy, or the recycling of proteins. The results also suggested that during these early months the excitatory neurons matured faster in the mutant organoids than in the controls.

Other experiments suggested that many of these changes may have been the by-product of a complex interaction between mutant tau, excitatory neuronal genes, and ELAVL4, a protein that controls gene activity by binding to ribonucleic acid (RNA) molecules.

"Our results suggest that the V337M mutant tau sets off a vicious cycle in the brain that puts excitatory neurons under great stress. It hastens the production of new proteins needed for maturation but prevents disposal of the proteins that are being replaced," Dr. Bowles said.

Further experiments supported this idea. For example, excitatory neurons in mutant organoids were less likely to survive in the presence of toxic levels of glutamate than those in control organoids. The researchers then found that this could be prevented by apilimod, an experimental drug designed to alter a cell's protein recycling system. In other words, the researchers saw no difference in levels of glutamate-induced cell death between mutant and control organoids when they treated samples with apilimod.

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