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NS/ Brain study on how to slow down climate change

Neuroscience biweekly vol. 48, 8th December — 22nd December


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Mentalizing with the future: Electrical stimulation of the right TPJ increases sustainable decision-making

by Benedikt P. Langenbach, Branislav Savic, Thomas Baumgartner, Annika M. Wyss, Daria Knoch in Cortex

When it comes to climate-friendly behaviour, there is often a gap between what we want and what we actually do. Although most people want to see climate change slowed down, many do not behave in an appropriately sustainable way. Researchers at the University of Bern have now used brain stimulation to demonstrate that the ability to sympathize with the future victims of climate change encourages sustainable behaviour.

Global climate change may be the biggest challenge faced by humanity today. Despite decades of warnings and political resolutions, however, sustainability remains a long way from being achieved.

“The fact that people aren’t acting in a more climate friendly way isn’t because we know too little about this critical situation, though.” explains Daria Knoch, Professor for Social Neuroscience at the University of Bern.

To find out more about the reasons that prevent us from acting sustainably, Daria Knoch and her team have conducted a neuroscientific study.

Experimental setup and design. Panel A depicts the fishing game: If the four participants forming the current generation (on the left) exceed the inter-generational sustainability threshold (dashed line) and extract more than 36 fish (9 fish each) the next group’s payoff was reduced by 80% (depicted by smaller, less valuable fish; top right). If a group stayed within the threshold’s bounds, the next generation got the full payoff (bottom right). Additionally, if the four players exceed the intra-generational sustainability threshold (not depicted) of 68 fish (17 fish each), their own payoff is reduced by 80%. Panel B shows the results of a simulation of the electric fields in the right TPJ. The electric field strength was .32 V/m, see Methods for details. Panel C shows the design of the study. Note that the order of stimulation site was counterbalanced. Stimulation was ongoing while participants engaged in the fishing game, the fairness rating, and the estimation of the other player’s extraction.

While some effects of global warming are already visible today, those affected more strongly will be people in the future who we do not know.

“It is precisely our inability to mentalise with these strangers that discourages climate-friendly action,” says Daria Knoch, commenting on the findings of the new study that she carried out with her research group in the “Social Neuro Lab” at the University of Bern.

During the study, participants received stimulation to a part of their brain which plays an important role for taking the perspective of others. This stimulation led to more sustainable behaviour.

During the experiment, participants in groups of four withdrew real money from a shared pool. Each participant decided for themself: the more money they withdrew from the pool, the more they ultimately had in their pocket. However, if the group of four withdrew too much money overall, this had consequences for the next group: the payment they received was much lower. Thus, the experiment mimicked a real situation in which the overuse of a resource has negative consequences for other people in the future.

While deciding on the amount of money to withdraw, some participants received a brain stimulation (experimental group): a non-invasive, harmless, mild electrical current was applied to the skull to increase the function of the stimulated brain area. The researchers in Bern stimulated an area which plays a strong role in taking the perspective of others, and discovered that it had a considerable impact: the stimulated individuals made more sustainable decisions than the participants without the stimulation (control group), by deciding not to withdraw an excessive amount of money from the pool.

“Applying brain stimulation to the general public is out the question, of course,” explains Benedikt Langenbach, lead author of the study and a former PhD student at the Social Neuro Lab. However, according to the researchers, the functioning brain area in question can also be enhanced, for example, through neurofeedback and meditation. According to Benedikt Langenbach, who now works at the University of Duisburg-Essen, additional strategies are also available to improve the forming of perspectives: “We know that people are more likely to empathise with someone — a victim of climate change, for example — if they are able to identify with them.”

Daria Knoch adds:

“Our neuroscientific findings can therefore help to make communication on the climate crisis more effective, for instance by giving those affected a name and a face instead of talking about an anonymous ‘future generation’.”

A genetically defined insula-brainstem circuit selectively controls motivational vigor

by Hanfei Deng, Xiong Xiao, Tao Yang, Kimberly Ritola, Adam Hantman, Yulong Li, Z. Josh Huang, Bo Li in Cell

A characteristic of depression is a lack of motivation. Cold Spring Harbor Laboratory (CSHL) Professor Bo Li, in collaboration with CSHL Adjunct Professor Z. Josh Huang, discovered a group of neurons in the mouse brain that influences the animal’s motivation to perform tasks for rewards. Dialing up the activity of these neurons makes a mouse work faster or more vigorously — up to a point. These neurons have a feature that prevents the mouse from becoming addicted to the reward. The findings may point to new therapeutic strategies for treating mental illnesses like depression that affect motivation in humans.

The anterior insular cortex is a region of the brain that plays a critical role in motivation. A set of neurons that activate a gene called Fezf2(Fezf2 neurons) in this area are active when mice are doing both physical and cognitive tasks. Li and his lab hypothesized that these neurons do not affect the mouse’s ability to do the task; rather, the brain cells influence the mouse’s motivational drive.

Mice were trained to lick a water bottle spout to receive a small sugar reward. When researchers dialed up the activity of these Fezf2 neurons, mice would lick more vigorously. If the neuron activity was dialed down, the mice would lick more slowly. The researchers saw a similar result in another experiment in which the mice ran on a wheel to receive a reward. The mice ran faster if the Fezf2 neurons were stimulated. The same effect occurred with other tasks.

Li and his team were surprised to discover a feature that prevents the mice from becoming addicted to the tasks and their rewards. When mice drank their fill of sugar water and were satiated, they would not lick or run faster to get more sugar, even if the researchers dialed up the activity of the Fezf2 neurons.

Finding a way to fine-tune the human equivalent of these neurons might help people struggling with motivation due to mental illnesses like depression. Li says,

“We want to selectively increase the motivation of the person so that they can do the things that they need to do, but we don’t want to create addictive drugs.”

The role of motor memory dynamics in structuring bodily self-consciousness

by Ryota Ishikawa, Saho Ayabe-Kanamura, Jun Izawa in iScience

Scientists and philosophers have pondered the nature of consciousness for centuries. But now, researchers from Japan have uncovered new information that challenges previous theories about the relationship between two elements of consciousness.

In a study published this month in iScience, researchers from the University of Tsukuba have revealed that when the perception of bodily self-consciousness is distorted, the recovery of body ownership can be predicted by different kinds of memories.

Bodily self-consciousness arises through a developmental process in which sensory information is integrated with mental representations of the body, and it has specifically been linked to the relationship between body ownership and agency (the sense of being able to control one’s actions at will). However, little is known about the development of body ownership and agency, or how these are restored after injury, something the researchers at the University of Tsukuba aimed to address.

“Clarifying how temporal and dynamic aspects of bodily self-consciousness change over time is crucial for understanding how it is developed,” says main author of the study Professor Jun Izawa. “Specifically, the speed of adaptive recovery in task performance can illuminate the relationship between adaptive adjustments to memory and the recovery of various aspects of bodily self-consciousness.”

To examine this, the researchers decreased the perception of body ownership and agency by inducing a visual distortion while participants grasped an object in a virtual reality environment. They then observed how the participants adapted their movements to the distortion over a sequence of trials, to recover their ability to perform the grasping task.

“We found that the recovery of body ownership was associated with a fast memory process, whereas that of agency was mainly associated with a slow memory process,” explains Professor Izawa.

Thus, while body ownership and agency were restored simultaneously following exposure to the visuomotor distortion, this recovery appears to have been based on two different systems for updating memory, with distinct time courses.

“Our results challenge the conventional framework that proposes that body ownership and agency exist on different hierarchical levels of self-consciousness,” says Professor Izawa. “Instead, the perception of causality and hierarchy between these two elements may be an illusion resulting from the neural processing of parallel streams of information.”

Previous studies have indicated that body ownership and agency are distinct, and that they may by causally related. However, this new information indicates that the relationship between these two senses may not be so simple. Instead, changes in bodily self-consciousness may depend on the interaction between multiple motor memory processes over various timescales. This information could facilitate the development of treatments aimed at recovering self-consciousness after illness or injury.

Setting the Stage for Speech Production: Infants Prefer Listening to Speech Sounds With Infant Vocal Resonances

by Linda Polka, Matthew Masapollo, Lucie Ménard in Journal of Speech, Language, and Hearing Research

A new study suggests that when parents’ babies talk to their infants, they might be helping them learn to produce speech.

The way we instinctively speak to babies — higher pitch, slower speed, exaggerated pronunciation — not only appeals to them, but likely helps them learn to understand what we’re saying. New research from the University of Florida suggests that baby talk can have another, previously unknown benefit: helping babies learn to produce their own speech. By mimicking the sound of a smaller vocal tract, the researchers think, we’re cluing babies in to how the words should sound coming out of their own mouths.

“It seems to stimulate motor production of speech, not just the perception of speech,” said Matthew Masapollo, Ph.D., an assistant professor in UF’s Department of Speech, Language, and Hearing Sciences and director of the UF Laboratory for the Study of Cognition, Action, and Perception of Speech in the College of Public Health and Health Professions. “It’s not just goo-goo ga-ga.”

In the study, the researchers changed the frequency sounds to mimic either an infant or adult vocal tract, and then tested how infants reacted. Six- to eight-month-old babies “displayed a robust and distinct preference for speech with resonances specifying a vocal tract that is similar in size and length to their own,” they wrote.

Four- to six-month old babies didn’t have that preference, suggesting that older babies’ dawning ability to control their voices and make words out of babble could be what makes the infant-like sounds more appealing.

Connected boxplots of infant mean listening times (in seconds) to the different vowel types presented in the current experiments.

Though baby talk may sound simple, it’s accomplishing a lot, says coauthor Linda Polka, Ph.D., of McGill University.

“We’re trying to engage with the infant to show them something about speech production,” she said. “We’re priming them to process their own voice.”

While parents are sometimes discouraged from engaging in baby talk, Masapollo and Polka’s research shows the patterns associated with that speaking style — which scientists call “infant-directed speech” — could be a key component in helping babies make words.

Association of Air Pollution and Physical Activity With Brain Volumes

by Melissa A. Furlong, Gene E. Alexander, Yann C. Klimentidis, David A. Raichlen in Neurology

A new study shows that people who do vigorous physical activities, like jogging or playing competitive sports, in areas with higher air pollution may show less benefit from that exercise when it comes to certain markers of brain disease. The markers examined in the study included white matter hyperintensities, which indicate injury to the brain’s white matter, and gray matter volume. Larger gray matter volumes and smaller white matter hyperintensity volumes are markers of overall better brain health.

Vigorous exercise may increase exposure to air pollution and prior studies have shown adverse effects of air pollution on the brain,” said study author Melissa Furlong, PhD, of the University of Arizona in Tucson. “We did show that physical activity is associated with improved markers of brain health in areas with lower air pollution. However, some beneficial effects essentially disappeared for vigorous physical activity in areas with the highest levels of air pollution. That’s not to say people should avoid exercise. Overall, the effect of air pollution on brain health was modest — roughly equivalent to half the effect of one year of aging, while the effects of vigorous activity on brain health were much larger — approximately equivalent to being three years younger.”

The study looked at 8,600 people with an average age of 56 from the UK Biobank, a large biomedical database. People’s exposure to pollution, including nitrogen dioxide and particulate matter, which are particles of liquids or solids suspended in the air, was estimated with land use regression. A land use regression study models air pollution levels based on air monitors and land use characteristics like traffic, agriculture and industrial sources of air pollution.

Participants’ air pollution exposures were categorized into four equal groups, from lowest air pollution to highest.

Each person’s physical activity was measured for one week with a movement-detecting device they wore called an accelerometer. Then researchers characterized their physical activity patterns depending on how much vigorous physical activity they got, ranging from none to 30 minutes or more per week.

People who got the greatest amounts of vigorous physical activity each week, on average, had 800 cm3 gray matter volume, compared to an average of 790 cm3 gray matter volume in people who did not get any vigorous exercise. Researchers showed that air pollution exposures did not alter the effects of physical activity on gray matter volume. However, researchers did find air pollution exposures altered the effects of vigorous physical activity when looking at white matter hyperintensities. After adjusting for age, sex and other covariates, researchers found that vigorous physical activity reduced white matter hyperintensities in areas of low air pollution, but these benefits were not found among those in high air pollution areas.

“More research is needed, but if our findings are replicated, public policy could be used to address people’s exposure to air pollution during exercise,” Furlong said. “For example, since a significant amount of air pollution comes from traffic, promoting running or bicycling along paths far from heavy traffic may be more beneficial.”

A limitation of the study is that it used air pollution values from one year only, and levels may vary from year to year.

Neurons in the human medial temporal lobe track multiple temporal contexts during episodic memory processing

by Hye Bin Yoo, Gray Umbach, Bradley Lega in NeuroImage

In a discovery that could one day benefit people suffering from traumatic brain injury, Alzheimer’s disease, and schizophrenia, UT Southwestern researchers have identified the characteristics of more than 100 memory-sensitive neurons that play a central role in how memories are recalled in the brain.

Bradley Lega, M.D., Associate Professor of Neurological Surgery, Neurology, and Psychiatry, said his findings, may point to new deep brain-stimulation therapies for other brain diseases and injuries.

“It sheds important light on the question, ‘How do you know you are remembering something from the past versus experiencing something new that you are trying to remember?’” said Dr. Lega, a member of the Peter O’Donnell Jr. Brain Institute.

Experimental design illustrated. a, Schematic of the verbal free recall task for each list. Every session in the study included at least four lists with one practice list before the actual session begins. b, Structure of each period, with timelines of an encoding and a recall event. A recall event counts 1 s of silence preceding a recollection. We analyze two windows spanning -1000 to -501 ms and -500 to -1 ms from recollection separately as earlier and later retrieval periods.

The most significant finding was that firing occurs with different timing relative to other brain activity when memories are being retrieved. This slight difference in timing, called “phase offset,” has not been reported in humans before. Together, these results explain how the brain can “re-experience” an event, but also keep track of whether the memory is something new or something previously encoded.

“This is some of the clearest evidence to date showing us how the human brain works in terms remembering old memories versus forming new memories,” Dr. Lega said.

His study identified 103 memory-sensitive neurons in the brain’s hippocampus and entorhinal cortex that increase their rate of activity when memory encoding is successful. The same pattern of activity returned when patients attempted to recall these same memories, especially highly detailed memories.

This activity in the hippocampus may have relevance to schizophrenia because hippocampal dysfunction underlies schizophrenics’ inability to decipher between memories and hallucinations or delusions. The neurons identified by Dr. Lega are an important piece of the puzzle for why this happens, said Carol Tamminga, M.D., Professor and Chair of Psychiatry and a national expert on schizophrenia.

“Hallucinations and delusions in people with a psychotic illness are actual memories, processed through neural memory systems like ‘normal’ memories, even though they are corrupted. It would be important to understand how to use this ‘phase offset’ mechanism to modify these corrupted memories,” Dr. Tamminga said.

An opportunity to learn more about human memory arose from surgeries where electrodes that were implanted in epilepsy’s patients’ brains to map the patients’ seizures could also be used to identify neurons involved in memory. In this study, 27 epilepsy patients who had the electrodes implanted at UT Southwestern and a Pennsylvania hospital participated in memory tasks to generate data for brain research.

The data analysis does not conclusively prove, but adds new credibility to important memory model called Separate Phases at Encoding And Retrieval (SPEAR) that scientists developed from rodent studies.

“It’s never been nailed down. It’s one thing to have a model; it is another thing to show evidence that this is what’s happening in humans,” Dr. Lega said.

The SPEAR model, which predicts the “phase offset” reported in the study, was developed to explain how the brain can keep track of new-versus-old experiences when engaged in memory retrieval. Previously, the only evidence in support of SPEAR came from rodent models.

Benefit of human moderate running boosting mood and executive function coinciding with bilateral prefrontal activation

Running may be a useful activity to undertake for better mental health. University of Tsukuba researchers have found that only ten minutes of moderate-intensity running increases local blood flow to the various loci in the bilateral prefrontal cortex — the part of the brain that plays an important role in controlling mood and executive functions. These findings may contribute to the development of a wider range of treatment recommendations to benefit mental health.

There’s clear evidence that physical activity has many benefits, such as the ability to improve mood, but in previous studies, cycling was often the form of exercise studied. Running, however, has always played an important role in the well-being of humans. The unique form and efficiency of human running, which includes the ability to sustain this form of exertion (i.e., by jogging as opposed to sprinting), and the evolutionary success of humans are closely linked.

Comparison in mood change [(post-session) — (pre-session)] between control and running: (a) arousal level difference and (b) pleasure level difference. The bottom, middle and top lines of each box indicate the 25th, 50th (median) and 75th percentiles, respectively. Whiskers above and below each box refer to the most extreme point within 1.5 times the interquartile range. Points above the whiskers are outliers. *** = p < 0.001.

Despite this fact, researchers had not yet looked closely at the effects of running on brain regions that control mood and executive functions.

“Given the extent of executive control required in coordinating balance, movement, and propulsion during running, it is logical that there would be increased neuronal activation in the prefrontal cortex and that other functions in this region would benefit from this increase in brain resources,” explains Professor Hideaki Soya.

To test their hypothesis, the research team used the well-established Stroop Color-Word Test and captured data on hemodynamic changes associated with brain activity while participants were engaged in each task. For example, in one task, incongruent information is shown, i.e., the word red is written in green, and the participant must name the color rather than read out the word. To do so, the brain must process both sets of information and inhibit the extraneous information. The Stroop interference effect was quantified by the difference in response times for this task and those for a simpler version of the task — stating the names of color swatches.

The results demonstrated that, after ten minutes of moderate-intensity running, there was a significant reduction in Stroop interference effect time. Furthermore, bilateral prefrontal activation had significantly increased during the Stroop task. After running, participants reported being in a better mood.

“This was supported by findings of coincident activations in the prefrontal cortical regions involved in mood regulation,” first author Chorphaka Damrongthai adds.

Cortical activation patterns during performance of the color-word matching Stroop task (CWST) in the pre-session of control and running. Presented data are average values between the pre-session of control and the pre-session of running. Baseline (2 s before trial onset) is set at zero and peak periods are indicated from 4 to 11 s after trial onset. Significant Stroop-interference-related cortical activations [incongruent — neutral] were found in all regions of interest (ROIs) indicating that the Stroop interference effect can be observed. The t-map demonstrates oxygenated hemoglobin (Oxy-Hb) signal change, t-values are indicated as in the color bar. Data are mean ± SE.

Given that many characteristics of the human prefrontal cortex are uniquely human, this study not only sheds light on the present benefits of running but also on the possible role that these benefits may have played in the evolutionary past of humans.

Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease

by Fang, J, Zhang, P, Zhou, Y et al. in Nature Aging

A study looking at the potential of repurposing licensed drugs for the treatment of Alzheimer’s disease has identified the erectile dysfunction drug sildenafil, brand name Viagra, as a candidate for future analysis.

The search for drugs that can treat the symptoms of Alzheimer’s disease effectively has become a long and costly project. The last major advance in our understanding of this condition arguably happened prior to the 21st century, with the identification of the role of the proteins tau and amyloid in the spread of Alzheimer’s through the brain.

Since then, numerous trials have been undertaken to test drugs based on the amyloid and tau hypotheses in patients with Alzheimer’s disease. From the early 2000s until last year, all had failed. While the qualified approval of the anti-amyloid monoclonal antibody aducanumab provides some hope that research into Alzheimer’s is at least aiming in the right direction, the immense cost and serial failure of prior trials have led to companies and academics examining alternative routes to drug development. One of these options is based on finding already-approved compounds that may be repurposed for Alzheimer’s disease.

A new study, armed with an innovative, computational drug development approach, has identified the erectile dysfunction drug sildenafil, known to millions of men around the world as Viagra, as a compound linked to a lower risk of Alzheimer’s disease. Viagra, approved in the US in 1998 and patented by Pfizer, is an artificial compound that was originally designed to treat cardiovascular disease. The drug did little to treat angina, but its unexpected and enervating side effects made it a worldwide success.

The new research was published in Nature Aging by senior author and Case Western Reserve University professor Feixiong Cheng and colleagues. The team built a dataset of genes, RNA molecules and proteins that have been linked to Alzheimer’s disease in previous studies. This was mapped onto a vast model of the human protein interactome — which records how protein molecules relate to each other at a molecular level during biochemical activity. The model captured over 350,000 interactions spread over 17,706 different proteins.

Cheng’s team then used this data as a canvas on which to sketch out the drug-target interactions of more than 1,600 drugs approved by the US Food and Drug Administration (FDA). Drugs were scored, with the top performing compounds having the strongest relationship to Alzheimer’s disease-linked molecules.

In total, the groups had created 13 different sub-datasets, which they called endophenotype modules, based on their data. They looked at which of the top 100 scoring drugs interacted with more than four of the modules. They whittled down the list to 21 drugs that had also been previously investigated in Alzheimer’s disease. These finalists had a huge range of approved uses: the anesthetic lidocaine featured, as did the anti-ALS drug riluzole and the muscle relaxant dantrolene. After ruling out compounds already under investigation for Alzheimer’s disease and those with insufficient patient data, Viagra was the only top performer left standing.

To make sure that their computational approach had some basis in real-life data, the team analyzed insurance claims from seven million Viagra users in the US. Prescription of Viagra was associated with a 69% reduction in the risk of Alzheimer’s diagnosis in the following six years. To examine what molecular mechanisms might explain this, the team dosed neurons in a dish derived from the stem cells of Alzheimer’s disease patients, showing that it increased the growth of neural connections and reduced the accumulation of tau protein.

The promise of these findings is a qualified one. The computational approach taken was not capable of establishing causality, meaning there was no way to conclusively say that taking Viagra reduced risk of Alzheimer’s disease in the insurance claim cohort.

Another significant factor is Viagra’s somewhat specialized indication. Only 2% of people claiming for the drug were women, who make up the majority of the Alzheimer’s disease patient population. Dr. Susan Kohlhaas, director of research at Alzheimer’s Research UK, who was not involved in the study said in a press release:

“While the researchers did look at the effect of sildenafil on females, there isn’t enough information to be able to accurately draw conclusions about its effect in females.

Kohlhaas also addressed the need for future experiments to back up the paper. “The researchers have conducted lab-based experiments to give an indication as to why the drug may impact diseases like Alzheimer’s, but these early-stage experiments would need follow-up in more thorough tests,” she said.

While Viagra’s reputation might drive the study into the headlines, it is the computational repurposing approach the researchers adopted that may yet prove most significant to drug discovery — providing a cheaper and faster route to potential treatments.

“Developing drugs for diseases like Alzheimer’s, which attack the brain, is a costly process and can take many years. Being able to repurpose a drug already licensed for other health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner,” said Kohlhaas.

Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation

by Meihua Jin, Hiroki Shiwaku, Hikari Tanaka, Takayuki Obita, Sakurako Ohuchi, Yuki Yoshioka, Xiaocen Jin, Kanoh Kondo, Kyota Fujita, Hidenori Homma, Kazuyuki Nakajima, Mineyuki Mizuguchi, Hitoshi Okazawa in Nature Communications

Just as a home security system can alert a homeowner to the presence of an intruder, a protein called polyglutamine binding protein-1 (PQBP1) found in brain cells can alert the body to the presence of “intruding” viruses like human immunodeficiency virus (HIV). Now, researchers in Japan have shed new light on the role of PQBP1 in the detection of dysfunctional proteins associated with neurodegenerative disorders.

In a new study published in Nature Communications, researchers from Tokyo Medical and Dental University (TMDU) have revealed the role of intracellular receptor PQBP1 in response to Tau, a protein found primarily in neurons that plays a key role in the progression of neurodegenerative disorders like Alzheimer’s disease.

PQBP1 has been previously shown to sense and bind HIV DNA and trigger an immune pathway known as the cGAS-STING pathway to initiate an inflammatory response. While PQBP1 has also been shown to interact with dysfunctional proteins such as those implicated in the neurodegenerative disorder Huntington’s disease, the specific role of PQBP1 in neurodegenerative inflammatory responses was unclear. To better understand this relationship, researchers from TMDU set out to clarify the nature of the interaction between PQBP1 and Tau.

“By characterizing the relationship between PQBP1 and Tau, we were able to clarify a mechanism of inflammation in the brain that functions in both viral infection and neurodegenerative disease,” says senior author of the study, Hitoshi Okazawa.

The researchers performed in vitro analyses using microglia, which are PQBP1-expressing immune cells found in the brain, to demonstrate that Tau interacts with PQBP1 and that this interaction drives an immune response via activation of the cGAS-STING pathway. Their study revealed that the PQBP1-cGAS-STING pathway functions in parallel with TREM2-mediated pathway, whose mutation is known to associate with Alzheimer’s disease genetically.

PQBP1 interacts with extrinsic Tau in microglia. a Schematic presentation of deletion mutants of tau and PQBP1 used for SPR and NMR analyses. N1/2 N-terminal domain, R1/2/3/4 C-terminal microtubule-binding domain, PRR proline-rich region, WWD WW domain, PRD polar amino acid-rich domain, IDP/IDR intrinsically disordered region. b Equilibrium binding curves of PQBP1 to Tau 410, Tau 441, Tau 410 P179A, Tau 410 P216A, and Tau 410 P179A/P216A monitored by SPR. Tau proteins were immobilized on sensor chip surfaces. The binding response at equilibrium was plotted against the concentration of PQBP1. Black, full-length PQBP1; red, PQBP1(1–94); blue, PQBP1 (94–176); green, PQBP1 (193–265). RU resonance unit. c 1H-15N HSQC spectra of Tau 1–150, 151–197, 198–243, 244–341, and 342–410 in the absence (black) and presence (red) of PQBP1(1–94). Amino acid residue numbers of tau are based on Tau 410. The molar ratio of Tau:PQBP1 (1–94) is 1:5. Residues showing significant chemical shift perturbation and line broadening of resonances are labeled in the HSQC spectra of Tau 151–197 and 198–243. Ctrl control, ppm parts per million. d Tau 410 amino acid sequence showing consensus motifs for interaction with PQBP1-WWD (red letter) and mutated prolines (underlined). e A representative western blot showing co-precipitation of tau with PQBP1 from a lysate of C57BL/6 microglia cultured for 3 days with 25 nM non-aggregated Tau-TAMRA (upper panels). Quantitative immunoprecipitation was performed with C57BL/6 microglia cultured for 3 days with 25 nM non-aggregated Tau-TAMRA. Input was the intensity of TAMRA-labeled Tau 410 in the C57BL/6 microglia lysate samples used for immunoprecipitation. Output was the intensity of TAMRA-labeled Tau 410 in samples after immunoprecipitation with anti-tau, anti-PQBP1, and human IgG. The fluorescence intensity of TAMRA-labeled Tau 410 was measured on a FLUOstar OPTIMA-6 microplate reader. n.s. not significant, AU arbitrary unit. N = 4 per group. P = 0.9963 (ctrl-IgG vs PQBP1), 0.8874 (ctrl-IgG vs tau), 0.9215 (PQBP1 vs tau), 9.63e−6 (PQBP1 vs ctrl-IgG), 3.69e−7 (tau vs ctrl-IgG). ##P < 0.01, n.s.P > 0.05 in Tukey’s HSD test. Box plots show the median, quartiles, and whiskers that represent data outside the 25th to 75th percentile range.

They went on to use a mouse model in which PQBP1 was conditionally inactivated in microglia to show that expression of PQBP1 is necessary for a Tau-induced inflammatory response in vivo.

“We were pleased to find that inactivating PQBP1 in microglia in the mouse model reduced brain inflammation in response to the injection of Tau into the brain,” says Okazawa.

The team further found that mutations in the PQBP1-binding regions of Tau reduced the inflammation in the brain in response to Tau injection. These findings indicate that PQBP1 may represent a potential target for the development of therapeutics for the treatment of Tau-mediated neurodegenerative diseases.

Low vitamin B12 but not folate is associated with incident depressive symptoms in community-dwelling older adults: a 4 year longitudinal study

by Laird E, O’Halloran AM, Molloy AM, et al. in British Journal of Nutrition

Scientists from The Irish Longitudinal Study on Ageing (TILDA) have published new research which examines the relationship between folate and vitamin B12 status and its associations with greater prevalence of depressive symptoms in a group of community-dwelling older adults. The study, published in the prestigious British Journal of Nutrition, shows that low vitamin B12 status is linked to depressive symptoms, but shows that folate is not associated with depression. The findings reveal pertinent information for older adults, public health and policymakers to better understand how to identify risk and adopt protective measures to enhance health outcomes for persons aged 50 and over.

Deficiency and low status of the B-vitamins such as folate and vitamin B12 are highly present in older people. In Ireland, one in eight older adults are reported to have low B12 status, while low dietary intake and low blood status have been reported throughout all age groups in the Irish population. Some of the negative consequences of low B12 status can include megaloblastic anaemia, impaired cognitive function, or damage to the protective covering (myelin sheath) that surrounds the nerve fibres of the brain. Understanding the link between folate or low B12 status and depression in later life is important as depression is a risk factor for functional decline, admission to residential care and early death.

The study uses data from TILDA, and examines participants aged 50 years and over who were assessed at Wave 1 of the study and who provided measurement of plasma folate and plasma B12 and screening for depression. Researchers observed that those with deficient-low B12 status had a 51% increased likelihood of developing depressive symptoms over 4 years.

Key Findings of the study

  • The study finds that low B12 status is associated with a significantly greater risk of depressive symptoms over four-year period, but no such associations were observed for folate.
  • These findings remained robust even after controlling for relevant adjusting factors such as physical activity, chronic disease burden, vitamin D status, cardiovascular disease and antidepressant use.
  • Researchers observed that those with deficient-low B12 status had a 51% increased likelihood of developing depressive symptoms over 4 years in this study.
  • Other factors that influence micronutrient status in older adults included obesity, medication use, smoking, wealth, gender and geographic location.
  • Researcher found that as age increased, the risk of depression decreased.
  • These findings are relevant given the high occurrence of incident depression and the high levels of low-deficient status of B12 in the older adult population in Ireland.
  • These observations also provide reassurance for food policy makers that fortification of foods to increase levels of these vitamins could have the potential for benefits in prevention of this condition.

Dr Eamon Laird, lead author of the study said:

This study is highly relevant given the high prevalence of incident depression in older adults living in Ireland, and especially following evidence to show that one in eight older adults report high levels of low B12 deficiency rates. There is a growing momentum to introduce a mandatory food fortification policy of B-vitamins in Europe and the UK, especially since mandatory food fortification with folic acid in the US has showed positive results, with folate deficiency or low status rates of just 1.2% in those aged 60 years and older. Our findings should provide further reassurance for policy makers to show that a food fortification policy could offer a potential means to aid the prevention of depressive symptoms in older adults and benefit overall health through the enrichment of food such as breakfast cereals with B12 vitamins and folate.

Professor Rose Anne Kenny, Principal Investigator of TILDA said:

TILDA is exceptional in the breadth of rich data available from its longitudinal dataset, which offers a unique opportunity to conduct strong evidence-based research and spot important changes in a group over time. A major strength of this study is that it is based on a large, nationally representative sample of older adults in Ireland, observed over four years. Moreover, researchers examined a well-characterised group and included a wide range of confounding factors including chronic disease, medications, lifestyle factors and other nutrient blood biomarkers to reveal robust findings. Given the rise in loneliness and depression in older adults after the onset of COVID-19 restrictions, this study highlights the importance of increasing B12 intake or supplementation to help mitigate against potential risk factors of depression in older adults.


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