Today (Wednesday 4 August) researchers in the US have published findings describing how levels of the hallmark Alzheimer’s protein, amyloid in midlife are linked to subsequent decline in memory and thinking in later life. The scientific publication, Neurology, published the results.

What we already know

Amyloid builds up in the brain during Alzheimer’s, creating sticky clumps that are thought to play a role in disease.

There are several different forms of the amyloid protein, some more sticky and harmful than others.

Research has already shown that people with Alzheimer’s also tend to have more amyloid of a harmful type in their blood than healthy people.

What did the researchers do?

In this study, the researchers looked at the levels of different forms of amyloid in blood samples from 2,284 people without memory problems in midlife – they had an average age of 59.

They found the ratio levels of amyloid measured in the blood helped predict whether someone went on to develop Alzheimer’s disease, or mild cognitive impairment in later life (with most people now in their 70s).

What our expert had to say?

Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said:
“Improving the accuracy of Alzheimer’s blood tests has long been a goal for researchers, but it’s a tricky task, as protein levels can be influenced by so many factors that differ between individuals.

“Alzheimer’s disease can get underway in the brain up to two decades before symptoms start to show. Drugs designed to target amyloid are the frontrunners in the race for better Alzheimer’s treatments and are likely to be most effective at these early disease stages. But it is very difficult to identify healthy people who will go on to develop symptoms years later. Blood tests like this could allow for rapid screening, and reduction of the numbers who would need more expensive PET scans before entering any future drug studies or receiving possible treatment.

“Although these findings have potential for supporting future research, exciting new developments in blood tests that focus on a different Alzheimer’s protein, tau, hold the most promise for supporting an Alzheimer’s diagnosis.

“A reliable blood test would be a huge boost for the dementia field. Now is a critical time to invest in research to realise the possible benefits of a blood test for Alzheimer’s and begin to test potential life-changing drugs earlier.”

Want to know more?

Visit http://alzres.uk/bloodtest to find out more about when we could see a blood test for Alzheimer’s disease.

You can read this research paper here.

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Reference: Kevin J. Sullivan et al, Association of Midlife Plasma Amyloid-β Levels With Cognitive Impairment in Late Life: The ARIC Neurocognitive Study, Neurology (2021). DOI: 10.1212/WNL.0000000000012482

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Provided by Alzheimer’s Research UK

People with autism spectrum disorder have difficulty interpreting facial expressions.

Using a neural network model that reproduces the brain on a computer, a group of researchers based at Tohoku University have unraveled how this comes to be.

The journal Scientific Reports published the results on July 26, 2021.

“Humans recognize different emotions, such as sadness and anger by looking at facial expressions. Yet little is known about how we come to recognize different emotions based on the visual information of facial expressions,” said paper coauthor, Yuta Takahashi.

“It is also not clear what changes occur in this process that leads to people with autism spectrum disorder struggling to read facial expressions.”

The research group employed predictive processing theory to help understand more. According to this theory, the brain constantly predicts the next sensory stimulus and adapts when its prediction is wrong. Sensory information, such as facial expressions, helps reduce prediction error.

The artificial neural network model incorporated the predictive processing theory and reproduced the developmental process by learning to predict how parts of the face would move in videos of facial expression. After this, the clusters of emotions were self-organized into the neural network model’s higher level neuron space – without the model knowing which emotion the facial expression in the video corresponds to.

The model could generalize unknown facial expressions not given in the training, reproducing facial part movements and minimizing prediction errors.

Following this, the researchers conducted experiments and induced abnormalities in the neurons’ activities to investigate the effects on learning development and cognitive characteristics. In the model where heterogeneity of activity in neural population was reduced, the generalization ability also decreased; thus, the formation of emotional clusters in higher-level neurons was inhibited. This led to a tendency to fail in identifying the emotion of unknown facial expressions, a similar symptom of autism spectrum disorder.

According to Takahashi, the study clarified that predictive processing theory can explain emotion recognition from facial expressions using a neural network model.

“We hope to further our understanding of the process by which humans learn to recognize emotions and the cognitive characteristics of people with autism spectrum disorder,” added Takahashi. “The study will help advance developing appropriate intervention methods for people who find it difficult to identify emotions.”

Publication Details:

• Title: Neural network modeling of altered facial expression recognition in autism spectrum disorders based on predictive processing framework
• Authors: Yuta Takahashi, Shingo Murata, Hayato Idei, Hiroaki Tomita & Yuichi Yamashita
• Journal: Scientific Reports
• DOI: 10.1038/s41598-021-94067-x

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Provided by Tohoku University

A study by an international research group co-led by UCL researchers has identified 15 novel biomarkers that are linked to late-onset dementias.

These biomarkers are proteins, which predict cognitive decline and subsequent increased risk of dementia already 20 years before the disease onset.

The proteins are related to immune system dysfunction, blood-brain-barrier dysfunction, vascular (blood vessel) pathologies, and central insulin resistance. Six of these proteins can be modified with currently available medications prescribed for conditions other than dementia. 

Lead author Dr Joni Lindbohm (UCL Epidemiology & Public Health and University of Helsinki) said: “These findings provide novel avenues for further studies to examine whether drugs targeting these proteins could prevent or delay the development of dementia.”

The results of the study have been published in the Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Amyloid beta and tau proteins have dominated pathophysiological research on what causes dementia, but to date prevention and treatment trials targeting these biomarkers have been unsuccessful. This has motivated researchers to search for other potential mechanisms that could predispose to dementia. Recent development of scalable platforms has made it possible to analyse a wide range of circulating proteins, which may reveal novel biological processes linked to dementias.

In this study the authors were able to analyse proteins with a novel large-scale protein panel from stored blood samples of the UK-based Whitehall II and US-based Atherosclerosis Risk in Communities (ARIC) studies collected 20 years ago. Using a panel of 5,000 proteins measured from plasma, the researchers identified proteins that predicted cognitive decline in five-yearly screenings and subsequent onset of clinical dementia. The 15 proteins predicted dementia in both the UK and US cohorts.

Senior author and Director of the Whitehall II study, Professor Mika Kivimäki (UCL Epidemiology & Public Health) said: “This new study is the first step in our five-year Wellcome Trust funded research programme. We will next examine whether the identified proteins have a causal association with dementia, and whether they are likely to be modifiable, and druggable.”

The ultimate aim of the research programme is to identify novel drug targets for dementia prevention.

The international team, involving academics from the UCL faculties of Population Health Sciences and Brain Sciences, included scientists from the UK, Finland, Sweden, US, and France.

Links

• Research paper in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association
• Whitehall II study

Images

• The two brain proteins previously known to play major roles in dementia diseases: beta-amyloid plaques (seen in brown) and tau (seen in blue) in the brain. Credit: National Institute on Aging, NIH, on Flickr

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Provided by UCL

While some students may think it’s a good idea to pull an all-nighter before an exam, conventional wisdom may be correct: A good night’s sleep may actually be more helpful, according to University of Michigan research.

U-M scientists Sara Aton and James Delorme found when mice are sleep-deprived, there is an increase in activity in inhibitory neurons in the hippocampus, an area of the brain essential for navigation, as well as for processing and storing new memories.

“Because these neurons limit activity in their neighbors, this physiological response makes it impossible to muster normal neuronal activity in the hippocampal structure,” said Aton, an associate professor in the U-M Department of Molecular, Cellular and Developmental Biology and a member of the U-M Center for RNA Biomedicine executive committee. “I always tell my students that an overnighter is not helping them prepare for an exam.”

The researchers’ results are published in the Proceedings of the National Academy of Sciences, and their findings could have implications for human performance and learning strategies.

Previous research has shown there is a sensitive window of time—a few hours following learning—during which mice have to sleep in order to fully consolidate a memory. During this period, neuronal activity must remain undisturbed in the hippocampus, and RNA transcription and translation within the neurons must occur normally. Aton and Delorme, formerly a U-M neuroscience graduate student, studied the possible links between changes in neurons’ activity after learning and changes in their protein translation.

First, Delorme investigated the interaction between sleeping and waking, hippocampal neuron activity, and activity-driven phosphorylation of S6, a component of ribosomes—tiny organelles which translate mRNA into protein. This phosphorylation event is thought to affect which mRNAs that are being translated into protein as neurons become more active. This regulation may be important for adapting to neurons’ ever-changing metabolic demands.

To do this, Delorme gave mice a fear stimulus. When mice were allowed to freely sleep following the stimulus, he saw that S6 phosphorylation increased in a part of the hippocampus called the dentate gyrus, the first region where memories begin to form.

But when the mice were deprived of sleep, Delorme found that phosphorylation decreased throughout the hippocampus. This disrupted the mice’s memories that otherwise would have been formed in response to the fear stimulus.

Delorme’s next question was whether this reduction in activity-driven S6 phosphorylation affected all neurons similarly after sleep loss. Using bioinformatics, he compared the abundance of mRNAs associated with phosphorylated S6-containing ribosomes. He also examined mRNA profiles under conditions of prior sleep or no sleep.

Delorme then collaborated with U-M Advanced Genomics core for the RNA sequencing. He observed that, after sleep deprivation, there was a significant increase in abundance of a type of RNA transcripts known to be present specifically in interneurons that express the neuropeptide somatostatin as well as the inhibitory neurotransmitter GABA.

This relative increase suggested that greater activity among somatostatin-containing interneurons inhibits surrounding neurons, and thus overall S6 phosphorylation in the hippocampus, acting as a gate that slows down their firing.

When they mimicked this inhibitory gating mechanism in freely sleeping mice, they were able to disrupt hippocampal activity and memory consolidation. In contrast, suppressing the activity of somatostatin-expressing interneurons after learning increased activity among dentate gyrus neurons and was beneficial to memory consolidation.

In disorders such as Alzheimer’s disease, where sleep difficulties are common, there could be a relation between the physiological mechanism described in this study and memory loss. But there could be a neuron protection function, or an adaptive psychological reaction against stressful memories, says Aton.

“Sleep loss could at times be therapeutic. For example, using sleep deprivation after a traumatic event could be a way to prevent post-traumatic stress syndrome,” she said.

This study opens the door to further investigate how manipulating the relative balance between the activity of excitatory and inhibitory neurons affects memory, as well as comparing how these mechanisms are affected between REM and non-REM sleep.

Featured image: Somatostatin-expressing interneurons in the mouse dentate gyrus, labeled with Brainbow 3.0, which labels each neuron a distinct color. cFos, labeled green, is present in the nuclei of surrounding pyramidal cells which are active during sleep. Image credit: Frank Raven

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Reference: James Delorme et al, Sleep loss drives acetylcholine- and somatostatin interneuron–mediated gating of hippocampal activity to inhibit memory consolidation, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2019318118

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Provided by University of Michigan

Researchers in Singapore have discovered that brain cells cannot maintain the cholesterol-rich myelin sheath that protects and insulates neurons in the absence of a protein called TDP-43. The study, which will be published August 4 in the Journal of Cell Biology (JCB), suggests that restoring cholesterol levels could be a new therapeutic approach for diseases associated with TDP-43.

The TDP-43 protein is linked to multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 plays many vital roles within cells, but, under certain circumstances, it can clump together to form toxic aggregates that damage cells and prevent TDP-43 from performing its normal functions. TDP-43 aggregates are found in the brains of most ALS patients and ~45% of FTD patients and are also linked to several other neurodegenerative disorders, including some cases of Alzheimer’s disease. The aggregates form not only in neurons, but also in other brain cell types such as oligodendrocytes. These latter cells protect neurons and speed up the transmission of nerve impulses by wrapping neurons in a fatty substance called myelin.

Shuo-Chien Ling and colleagues at the Yong Loo Lin School of Medicine, National University of Singapore, have previously shown that oligodendrocytes need TDP-43 to survive and wrap neurons in myelin. “Specifically, we found that mice with oligodendrocytes lacking TDP-43 develop progressive neurological phenotypes leading to early lethality. These phenotypes were accompanied by the death of oligodendrocytes and progressive loss of myelin,” Ling says.

In the new study, Ling and colleagues find that one reason oligodendrocytes are dysfunctional in the absence of TDP-43 is that they are unable to synthesize or take up the cholesterol they need to sustain myelin production.

Cholesterol is such a major component of myelin that 25% of the body’s total cholesterol can be found in the central nervous system. Oligodendrocytes are known to synthesize large amounts of cholesterol for themselves, but they can also acquire it from other brain cells called astrocytes. Ling and colleagues determined that, in the absence of TDP-43, oligodendrocytes lack many of the enzymes required to synthesize cholesterol, and also have reduced levels of the low density lipoprotein receptor that can take in cholesterol from outside the cell. Supplementing these TDP-43–deficient cells with cholesterol restored their ability to maintain the myelin sheath.

Similar defects in cholesterol metabolism may occur in patients, where the formation of aggregates might prevent TDP-43 from performing its normal functions. Ling and colleagues analyzed brain samples from FTD patients and found that their oligodendrocytes produced lower amounts of two key enzymes required for cholesterol synthesis, while the low density lipoprotein receptor was incorporated into TDP-43 aggregates.

“Our results indicate that simultaneous disruption of cholesterol synthesis and uptake is likely one of the causes of the demyelination phenotype observed in mice with TDP-43–deficient oligodendrocytes, and suggest that defects in cholesterol metabolism may contribute to ALS and FTD, as well as other neurodegenerative diseases characterized by TDP-43 aggregates,” Ling says.

Drugs that modulate cholesterol metabolism might therefore be a novel therapeutic strategy to treat these diseases, the researchers suggest.

Featured image: Compared with a normal cell (left), an oligodendrocyte lacking TDP-43 (center) produces less myelin (green) because it is unable to synthesize or take up sufficient amounts of cholesterol. Supplementing TDP-43–deficient cells with cholesterol (right) restores myelin production. Credit: ©2021 Ho et al. Originally published in Journal of Cell Biology, 10.1083/jcb.201910213

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Reference: Wan Yun Ho et al, TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination, Journal of Cell Biology (2021). DOI: 10.1083/jcb.201910213

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Provided by Rockefeller University Press

Treating mice that have a Parkinson’s disease-causing mutation with a small molecule compound restores the removal of damaged mitochondria from their brain cells, shows a study published today in eLife.

The findings may help explain what goes wrong in dopamine-producing brain cells in people with mutations that cause Parkinson’s disease.

Parkinson’s disease is caused by the progressive loss of brain cells that produce dopamine. This causes the hallmark symptoms of the disease, including tremors, rigid movements, sleep problems and dementia.

“Scientists believe the death of these cells in people with Parkinson’s disease is caused, in part, by the failure of a quality control mechanism that removes damaged energy-producing structures in the cells called mitochondria,” explains first author Francois Singh, Postdoctoral Research Assistant at the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC PPU), University of Dundee, Scotland, UK. “This failure to recycle damaged mitochondria is detrimental to the health of brain cells.”

To learn more, Singh and colleagues teamed up with scientists from the Division of Signal Transduction Therapy, a consortium of academia and pharmaceutical companies. Together they used cutting-edge techniques to observe mitochondria recycling in the brains of mice that have the most common Parkinson’s disease-causing mutation in a gene called LRRK2.

Their experiments showed that damaged mitochondria are not efficiently removed in the animals’ dopamine-producing brain cells, and that damaged components in other types of brain cells are recycled. This may explain why dopamine-producing brain cells are selectively lost in Parkinson’s disease and why the symptoms are all linked to a lack of dopamine.

The mutation in the LRRK2 gene results in the production of a hyperactive version of the protein. Given this, the team treated the mice with a small molecule that inhibits the hyperactive protein and found that it restored mitochondria recycling in the animals’ dopamine-producing brain cells.

The authors say these results are an exciting step forward in the quest to understand mechanisms responsible for this currently incurable disease. These results should help drive and focus research in this area.

“Not only have we discovered new biology, but we have also shown that an LRRK2 inhibitor can rescue a mitochondrial defect related to Parkinson’s disease,” concludes senior author Ian Ganley, MRC Investigator and Scientific Programme Leader at MRC PPU, University of Dundee. “These findings highlight the significant benefit of academic-industrial collaborations that will hopefully accelerate the development of new treatments for Parkinson’s disease.”

Featured image: Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson’s disease. Credit: Wikipedia

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Reference: Francois Singh et al, Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice, eLife (2021). DOI: 10.7554/eLife.67604

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Provided by eLife

A team of scientists has uncovered a system in the brain used in the processing of information and in the storing of memories—akin to how railroad switches control a train’s destination.

A team of scientists has uncovered a system in the brain used in the processing of information and in the storing of memories—akin to how railroad switches control a train’s destination. The findings offer new insights into how the brain functions.

“Researchers have sought to identify neural circuits that have specialized functions, but there are simply too many tasks the brain performs for each circuit to have its own purpose,” explains André Fenton, a professor of neural science at New York University and the senior author of the study, which appears in the journal Cell Reports. “Our results reveal how the same circuit takes on more than one function. The brain diverts ‘trains’ of neural activity from encoding our experiences to recalling them, showing that the same circuits have a role in both information processing and in memory.”

This newly discovered dynamic shows how the brain functions more efficiently than previously realized.

“When the same circuit performs more than one function, synergistic, creative, and economic interactions become possible,” Fenton adds.

To explore the role of brain circuits, the researchers examined the hippocampus—a brain structure long known to play a significant role in memory—in mice. They investigated how the mouse hippocampus switches from encoding the current location to recollecting a remote location. Here, mice navigated a surface and received a mild shock if they touched certain areas, prompting the encoding of information. When the mice subsequently returned to this surface, they avoided the area where they’d previously received the shock–evidence that memory influenced their movement.

The analysis of neural activity revealed a switching in the hippocampus. Specifically, the scientists found that a certain type of activity pattern in the population of neurons known as a dentate spike, which originates from the medial entorhinal cortex (DSM), served to coordinate changes in brain function.

“Railway switches control each train’s destination, whereas dentate spikes switch hippocampus information processing from encoding to recollection,” observes Fenton. “Like a railway switch diverts a train, this dentate spike event diverts thoughts from the present to the past.”

The artistic rendering of this process (above) is available on Google Drive.

This research was supported by grants from the National Institutes of Health (R01NS105472 and R01MH099128).

Featured image credit: MF3d/Getty Images

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Reference: Dentate spikes and external control of hippocampal function, Cell Reports (2021). DOI: 10.1016/j.celrep.2021.109497

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Provided by NYU