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Scientists show how excess tau protein contributes to Alzheimer’s

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Exocytosis and endocytosis are key steps in vesicle recycling. Exocytosis increases the surface area of the presynaptic terminal membrane, and endocytosis reduces the surface area

Alzheimer’s disease is a brain disorder that causes neurons to die, slowly destroying memory and thinking skills.

It’s the most common type of dementia, impacting an estimated 50 million people worldwide, and is a particularly serious issue for Japan’s super-aged society.

Despite its prevalence, the causes remain poorly understood and treatment options are limited.

Now, a team of scientists in Japan has revealed how excess tau – a key protein implicated in Alzheimer’s disease – impairs signalling between neurons in the brains of mice.

The study, published recently in eLife, could open new pathways for treating the symptoms and even halting the progression of Alzheimer’s disease and other neurodegenerative disorders.

About tau

Tau is produced in neurons, where it binds to and promotes the assembly of microtubules – long, thin filaments that maintain cell structure and provide pathways for transport within the cell.

Tau usually exists in either this bound state, or it is dissolved in the liquid that fills the cell.

However, in some neurological disorders, most famously in Alzheimer’s disease, levels of soluble tau in certain brain regions become too high, and it aggregates into insoluble structures called neurofibrillary tangles.

“A lot of scientists focus on the impact of these visible neurofibrillary tangles that are a hallmark of Alzheimer’s, but actually, it’s the invisible levels of soluble tau that correlate most closely with cognitive decline,” said Professor Tomoyuki Takahashi, senior author of the study, and head of the Cellular and Molecular Synaptic Function Unit at OIST.

Mammalian brains

The research began ten years ago, when his team looked at the effect of high levels of soluble tau on signal transmission at the calyx of Held – the largest synapse in mammalian brains.

Synapses are the places where two neurons make contact and communicate.

When an electrical signal arrives at the end of a presynaptic neuron, chemical messengers, known as neurotransmitters, are released from membrane ‘packets’ called vesicles into the gap between neurons.

When the neurotransmitters reach the postsynaptic neuron, they trigger a new electrical signal.

Using mice, Professor Takahashi’s research team injected soluble tau into the presynaptic terminal at the calyx of Held and found that electrical signals generated in the postsynaptic neuron dramatically decreased.

The scientists then fluorescently labelled tau and microtubules and saw that the injected tau caused new assembly of many microtubules in the presynaptic terminal.

No effect

However, when they injected a mutant tau protein instead that lacked the binding site necessary to assemble microtubules, there was no effect on synaptic transmission.

“This told us that the decrease in synaptic signalling was clearly linked to these newly assembled microtubules,” explained Professor Takahashi.

A second important clue was that elevated tau only decreased the transmission of high-frequency signals, while low-frequency transmission remained unchanged. High-frequency signals are typically involved in cognition and movement control.

The researchers suspected that such a selective impact on high-frequency transmission might be due to a block on vesicle recycling.

Vesicle recycling is a vital process for the release of neurotransmitters across the synapse since synaptic vesicles must fuse with the presynaptic terminal membrane, in a process called exocytosis.

These vesicles are then reformed by endocytosis and refilled with neurotransmitter to be reused.

If any of the steps in vesicle recycling are blocked, it quickly weakens high-frequency signals, which require the exocytosis of many vesicles.

Next step

The scientists found that high levels of soluble tau primarily impaired endocytosis. The lack of reformed vesicles impaired recycling and eventually slowed down exocytosis as a secondary effect.

Importantly, the researchers found that a drug called nocodazole, which blocks new microtubule assembly, prevented injected tau from impairing endocytosis.

The next step for the researchers was to figure out exactly how an excess of microtubules caused a block of endocytosis.

While searching for a link between microtubules and endocytosis, the team realized that dynamin, a large protein that cuts off vesicles from the surface membrane at the final step of endocytosis, was actually discovered as a protein that binds to microtubules, although little is known about the binding site.

When the scientists fluorescently labelled tau, microtubules and dynamin, they found that presynaptic terminals that had been injected with tau showed an increase of bound dynamin, preventing the protein from carrying out its role in endocytosis.

Normal level

Finally, the team created many peptides with matching sequences of amino acids to parts of the dynamin protein, to see if any of them could prevent dynamin from binding to the microtubules, and therefore rescue the signaling defects caused by tau protein.

When one of these peptides, called PHDP5, was injected along with tau, endocytosis and synaptic transmission remained close to a normal level.

Moving forward, the researchers plan to test this peptide in Alzheimer mouse models that have increased levels of soluble tau.

These mice lose their ability to learn and form new memories around six to eight months old, and the team hope that the peptide can prevent or reverse this memory impairment.

“To this end, we must modify PHDP5 so that it can penetrate the blood brain barrier. If this peptide works in these mice models, it can serve as an effective therapeutic tool for Alzheimer’s disease,” said Professor Takahashi.

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On a mission to show that hearing loss is not inevitable

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The world’s largest investigation into the effectiveness of hearing training kicks off this week – as part of a movement to prove that hearing loss is not an inevitable part of ageing.

The research project aims to attract a minimum of 10,000 participants to better understand how hearing training impacts auditory processing skills like speech comprehension and the ability to locate where sounds are coming from.

Researchers are interested in the impact of hearing training on users who start training with different hearing ability levels, as well as training adherence in groups with different attitudes to smartphone technology.

Their aim is to find new ways to deliver and improve auditory training at scale and for a wider range of hearing skills; and to measure factors which influence training engagement.

The research is led by health tech firm Eargym. Co-founder Andy Shanks says:  Contrary to popular belief, hearing loss is not an inevitable consequence of ageing. We can take steps to improve and protect our hearing throughout our lives, yet preventative measures like hearing training have traditionally been under-researched.

“Our data shows the transformative impact hearing training can have on our ability to process sounds. Now, we want to deepen and widen our research and use our platform to make hearing training even more effective and accessible. Imagine improving and maintaining your hearing by up to 20% or more: it could make a big difference to the lives of so many people.”

The games on the Eargym app include a “busy barista” exercise, where users must discern speech over a cafe’s bustling background noise; and a “sound seeking” exercise, where users make their way through forests, jungles and oceans to locate the sources of different sounds. Each game is designed to be immersive and to help users practise specific auditory processing skills regularly.

Eargym was set up by former NHS CEO Amanda Philpott and DJ Andy Shanks in 2020, after they were both diagnosed with hearing loss. Amanda has moderate age related hearing loss, whilst Andy has “notch” or noise-induced hearing loss due to DJ-ing. Both found hearing loss isolating and it impacted their ability to socialise and communicate. They created eargym to empower others to better understand their hearing health and take proactive steps to protect it.

Hearing loss currently affects 18 million adults in the UK, with around one billion young people at risk of developing hearing loss due to increased use of headphones. Hearing loss is closely associated with increased dementia risk. Despite this, people wait an average ten years before seeking help for hearing loss.

Eargym plans to publish the findings of its research in early 2025.

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Interview: Exploring electrical stimulation for Parkinson’s disease

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The STEPS II study is investigating functional electrical stimulation (FES) in people with Parkinson’s disease to help improve their walking. Dr Paul Taylor, co-founder and Clinical Director of Odstock Medical Ltd (OML), spoke to Agetech World to tell us more.

Bradykinesia – slowness of movement which can lead to difficulty walking – affects many people living with Parkinson’s disease. The symptom can cause Parkinson’s patients to walk or move slowly, increasing the risk of falls, leading to a reduced quality of life and an increased dependence on others. 

Funded by the National Institute for Health and Care Research, sponsored by Salisbury NHS Foundation Trust, and managed by the University of Plymouth’s Peninsula Clinical Trials Unit, the STEPS II study is exploring the use of an FES device in Parkinson’s patients to help improve bradykinesia. 

The FES device, which has been pioneered by Salisbury researchers as a drop foot treatment for stroke and MS patients, is attached to the patient’s leg and produces small electrical impulses that improve movement.

“If you have Bradykinesia you’re moving slowly. The predominant treatment for Parkinson’s is medication and these can be very effective, but they have the problem of not working all the time,” explains Taylor, co-founder of Odstock Medical Ltd, a company owned by Salisbury NHS Foundation Trust.

”The effects of the drugs will wear off and after a period of time they become less effective, so, there’s a need for improvement.”

Taylor explains that deep brain stimulators are currently available, however, they are very invasive, expensive and can be risky. 

“We’re trying to do something which is a bit simpler and cheaper, which may possibly be able to help people at an earlier stage of Parkinson’s,” Taylor says.

“We’re stimulating the common peroneal nerve, which is the nerve that goes down the leg to the muscles, using a device called a drop foot stimulator. The device is commonly used for stroke and multiple sclerosis.”

A small feasibility study has already been conducted, which showed that FES can help patients walk faster and reduce some symptoms of Parkinson’s. 

In the STEPS II study, researchers hope to confirm the long-term effects of FES on walking speed and daily life with 234 participants at sites across Salisbury, Birmingham, Prestwick, Leeds, Swansea and Carlisle.

Taylor continues: “Our original idea was that we could use electrical stimulation to overcome freezing – which is the effect where people with Parkinson’s will stop walking, particularly when they come to doorways or very narrow areas. It’s to do with the processing of information from the outside world. 

“We wanted to see if we could use electrical stimulation to overcome that freezing and, to a certain extent, we did find that is the case for some patients, but more commonly and with a greater number of patients FES affected bradykinesia – speeding up their movement and helping with more effective walking.”

For the STEPS II study, participants will be randomised into a care as normal group, or a care as normal plus FES group. They will use the stimulator if they are in the FES group for 18 weeks, then the stimulator is taken away, with patients followed up one month later to see if the effects are continued.

Measurements of walking speed and movement will be analysed, along with sensory perception, balance, coordination, muscle strength, as well as secondary effects such as how the device impacts daily living and quality of life.

OML has established clinics around the country with trained therapists where the device will be used if the study is successful. 

“There’s a network of clinics already experienced in using the treatment so we plan to reach those clinics to include Parkinson’s patients in their cohorts,” says Taylor. “Then we’ll work with our contacts to see if we can get it overseas as well.”

OML is currently recruiting participants for the study, to find out more please visit: https://www.plymouth.ac.uk/research/penctu/steps-2 

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Quit Googling to stave off dementia onset, expert urges

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Resisting the temptation to search the web for information that could otherwise be recalled be exercising your brain could help to reduce the risk of dementia.

That is according to Canadian academic Professor Mohamed I. Elmasry who believes simple daily habits such as afternoon naps, memory ‘workouts’ and not reaching for a smartphone can increase the odds of healthy aging.

His new book, iMind: Artificial and Real Intelligence, says the focus has shifted too far away from RI (natural, or real) intelligence in favour of AI (machine, or artificial) intelligence. Elmasry instead calls us to nurture our human mind which, like smartphones, has ‘hardware’, ‘software’ and ‘apps’ but is many times more powerful – and will last much longer with the right care.

Professor Elmasry, an internationally recognised expert in microchip design and AI, was inspired to write the book after the death of his brother-in-law from Alzheimer’s and others very close to him, including his mother, from other forms of dementia.

Although he says that smart devices are ‘getting smarter all the time’, he argues in iMind that none comes close to ‘duplicating the capacity, storage, longevity, energy efficiency, or self-healing capabilities of the original human brain-mind’.

He writes that: “The useful life expectancy for current smartphones is around 10 years, while a healthy brain-mind inside a healthy human body can live for 100 years or longer.

“Your brain-mind is the highest-value asset you have, or will ever have. Increase its potential and longevity by caring for it early in life, keeping it and your body healthy so it can continue to develop.

“Humans can intentionally develop and test their memories by playing ‘brain games,’ or performing daily brain exercises. You can’t exercise your smartphone’s memory to make it last longer or encourage it to perform at a higher level.”

In iMind: Artificial and Real Intelligence Professor Elmasry shares an anecdote about his grandchildren having to use the search engine on their smartphones to name Cuba’s capital—they had just spent a week in the country with their parents.

The story illustrates how young people have come to rely on AI smartphone apps instead of using their real intelligence (RI), he says, adding: “A healthy memory goes hand-in-hand with real intelligence. Our memory simply can’t reach its full potential without RI.”

Published by Routledge, iMind: Artificial and Real Intelligence includes extensive background on the history of microchip design, machine learning and AI and their role in smartphones and other technology.

The book also explains how both AI and human intelligence really work, and how brain function links the mind and memory. It compares the human mind and brain function with that of smartphones, ChatGPT and other AI-based systems.

Drawing on comprehensive existing research, iMind aims to narrow the knowledge gap between real and artificial intelligence, to address the current controversy around AI, and to inspire researchers to find new treatments for Alzheimer’s, other neurodegenerative conditions and cancer.

It argues that current or even planned AI cannot match the capabilities of the human brain-mind for speed, accuracy, storage capacity and other functions. Healthy aging, Professor Elmasry notes, is as important as climate change but doesn’t attract a fraction of the publicity.

He calls for policymakers to adopt a series of key reforms to promote healthy aging. Among such changes, he suggests that bingo halls could transition from their sedentary entertainment function to become active and stimulating learning centers.

As well as napping to refresh our memories and other brain and body functions, he also outlines a series of practical tips to boost brain power and enhance our RI (Real Intelligence).

These include building up ‘associative’ memory – the brain’s ‘dictionary of meaning’ where it attaches new information to what it already knows. Try reading a book aloud, using all of your senses instead of going on autopilot and turning daily encounters into fully-lived experiences.

Other techniques include integrating a day for true rest into the week, reviewing your lifestyle as early as your 20s or 30s, adopting a healthy diet, and eliminating or radically moderating alcohol consumption to reduce the risk of dementia.

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