How age opens the gates for Alzheimer’s

With advancing age, highly-evolved brain circuits become susceptible to molecular changes that can lead to neurofibrillary tangles — a hallmark of Alzheimer’s Disease, Yale researchers report the week of March 17 in the Proceedings of the National Academy of Sciences.

The findings not only help to explain why age is such a large risk factor for Alzheimer’s, but why the higher brain circuits regulating cognition are so vulnerable to degeneration while the sensory cortex remains unaffected.

“We hope that understanding the key molecular alterations that occur with advancing age can provide new strategies for disease prevention,” said Amy F.T. Arnsten, professor of neurobiology and one of the senior authors of the study.

Neurofibrillary tangles are made from a protein called tau, which becomes sticky and clumps together when modified in a process called phosphorylation. The Yale study found that phosphorylated tau collects in neurons in higher brain circuits of the aging primate brain, but does not accumulate in neurons of the sensory cortex. Phosphorylated tau collects in and near the excitatory connections called synapses where neurons communicate and can spread between cells in higher brain circuits, the study found.

The study led by Yale researchers Becky C. Carlyle, Angus Nairn, Arnsten and Constantinos D. Paspalas found clues about what causes tau to become phosphorylated with advancing age. They uncovered age-related changes in the molecular signals that control the strength of higher cortical connections. In young brains, an enzyme called phosphodiesterase PDE4A sits near the synapse where it inhibits a chemical “vicious cycle” that disconnects higher brain circuits when we are in danger, switching control of behavior to more primitive brain areas. They further found that PDE4A is lost in the aged prefrontal association cortex, unleashing a chemical cascade of events that increase the phosphorylation of tau. This process may be amplified in humans, where high order cortical neurons have even more excitatory connections, leading to tangle formation and ultimately cell death.

“This insight into one pathway by which tau may influence the onset and progression of Alzheimer’s disease takes us a step closer to unraveling this complex and devastating disorder,” said Dr. Molly Wagster, of the National Institutes of Health, a co-funder of the research.

The new study may also help to explain why head injury is a risk factor for Alzheimer’s, as it may also increase the activity of the chemical  “vicious cycle.”

“Now that we begin to see what makes neurons vulnerable, we may be able to protect cells with treatments that mimic the protective effects of PDE4A,” said Arnsten.

How a small worm may help the fight against Alzheimer’s

Scientists at the Max Planck Institute for Biology of Ageing in Cologne have found that a naturally occurring molecule has the ability to enhance defense mechanisms against neurodegenerative diseases. Feeding this particular metabolite to the small round worm Caenorhabditis elegans, helps clear toxic protein aggregates in the body and extends life span.

During ageing, proteins in the human body tend to aggregate. At a certain point, protein aggregation becomes toxic, overloads the cell, and thus prevents it from maintaining normal function. Damage can occur, particularly in neurons, and may result in neurodegenerative diseases like Alzheimer’s, Parkinson’s or Huntington’s disease. By studying model organisms like Caenorhabditis elegans, scientists have begun to uncover the mechanisms underlying neurodegeneration, and thus define possible targets for both therapy and prevention of those diseases. “Although we cannot measure dementia in worms“, explains Martin Denzel of the Max Planck Institute for Biology of Ageing, “we can observe proteins that we also know from human diseases like Alzheimer’s to be toxic by measuring effects on neuromuscular function. This gives us insight into how Alzheimer actually progresses on the molecular level“.

Now, the scientists Martin Denzel, Nadia Storm, and Max Planck Director Adam Antebi have discovered that a substance called N-acetylglucosamine apparently stimulates the body’s own defense mechanism against such toxicity. This metabolite occurs naturally in the organism. If it is additionally fed to the worm, “we can achieve very dramatic benefits“, says Denzel. “It is a broad-spectrum effect that alleviates protein toxicity in Alzheimer’s, Parkinson’s and Huntington’s disease models in the worm, and it even extends their life span.“

This molecule apparently plays a crucial role in quality control mechanisms that keep the body healthy. It helps the organism to clear toxic levels of protein aggregation, both preventing aggregates from forming and clearing already existing ones. As a result, onset of paralysis is delayed in models of neurodegeneration - How exactly the molecule achieves this effect is yet to be uncovered. “And we still don’t know whether it also works in higher animals and humans“, says Antebi. “But as we also have these metabolites in our cells, this gives good reason to suspect that similar mechanisms might work in humans.”

Scientists discover hormone released after exercise can ‘predict’ biological age

Scientists from Aston University have discovered a potential molecular link between Irisin, a recently identified hormone released from muscle after bouts of exercise, and the ageing process.

Irisin, which is naturally present in humans, is capable of reprograming the body’s fat cells to burn energy instead of storing it. This increases the metabolic rate and is thought to have potential anti-obesity effects which in turn could help with conditions such as type-2 diabetes.

The research team led by Dr James Brown have proven a significant link exists between Irisin levels in the blood and a biological marker of ageing called telomere length. Telomeres are small regions found at the end of chromosomes that shorten as cells within the body replicate. Short telomere length has been linked to many age-related diseases including cancer, heart disease and Alzheimer’s disease.

Using a population of healthy, non-obese individuals, the team has shown those individuals who had higher levels of Irisin were found to have longer telomeres. The finding provides a potential molecular link between keeping active and healthy ageing with those having higher Irisin levels more ‘biological young’ than those with lower levels of the hormone.

Dr James Brown from Aston’s Research Centre for Healthy Ageing, said; “Exercise is known to have wide ranging benefits, from cardiovascular protection to weight loss. Recent research has suggested that exercise can protect people from both physical and mental decline with ageing. Our latest findings now provide a potential molecular link between keeping active and a healthy ageing process.”

The Aston Research Centre for Healthy Ageing takes a multidisciplinary approach to successful ageing by asking how technological, therapeutic and psychosocial strategies can be employed to understand and arrest age-related decline and degeneration.

Your Brain Is Fine-Tuning Its Wiring Throughout Your Life

The white matter microstructure, the communication pathways of the brain, continues to develop/mature as one ages. Studies link age-related differences in white matter microstructure to specific cognitive abilities in childhood and adulthood.

Most prior studies, however, did not include individuals from the entire life span or evaluated a limited section of white matter tracts. This knowledge gap prompted a new study published this week in Biological Psychiatry.

Dr. Bart Peters, of the Zucker Hillside Hospital, and his colleagues investigated the relationship of age and neurocognitive performance to nine white matter tracts from childhood to late adulthood.

To accomplish this, they recruited 296 healthy volunteers who ranged from 8 to 68 years of age. The participants completed a comprehensive battery of tests designed to measure their cognitive functioning, including speed, attention, memory, and learning. They also underwent a non-invasive diffusion tensor imaging scan, a technology that allowed the researchers to create maps of the 9 major white matter tracts under investigation.

The combination of this data allowed them to identify the neurocognitive correlates of each white matter tract in relation to its unique aging pattern.

They found that, from childhood into early adulthood, differences in fractional anisotropy – a measure of connectivity – of the cingulum were associated with executive functioning, whereas fractional anisotropy of the inferior fronto-occipital fasciculus was associated with visual learning and global cognitive performance via speed of processing.

"Our study identified key brain circuits that develop during adolescence and young adulthood that are associated with the growth of learning, memory and planning abilities. These findings suggest that young people may not have full capacity of these functions until these connections have completed their normal trajectory of maturation beyond adolescence," explained Peters.

"Our brain is changing throughout our lives. These changes underlie the capacities that emerge and are refined through adulthood," commented Dr. John Krystal, Editor of Biological Psychiatry. “There are clues that the steps that we take to preserve our medical health and stimulate our minds also serve to further refine and maintain these connections. For good reasons, attending to brain health is increasingly a focus of healthy aging.”

In addition, many individuals diagnosed with psychiatric disorders suffer with neurocognitive dysfunction as part of their illness, which is particularly difficult to alleviate with currently available treatments. Studies such as this may help to identify specific brain circuits/pathways that could serve as potential targets for treatment interventions.

Forget about forgetting – The elderly know more and use it better

What happens to our cognitive abilities as we age? If your think our brains go into a steady decline, research reported this week in the Journal Topics in Cognitive Science may make you think again. The work, headed by Dr. Michael Ramscar of Tübingen University, takes a critical look at the measures usually thought to show that our cognitive abilities decline across adulthood. Instead of finding evidence of decline, the team discovered that most standard cognitive measures, which date back to the early twentieth century, are flawed. “The human brain works slower in old age,” says Ramscar, “but only because we have stored more information over time.”

Computers were trained, like humans, to read a certain amount each day, and to learn new things. When the researchers let a computer “read” only so much, its performance on cognitive tests resembled that of a young adult. But if the same computer was exposed to the experiences we might encounter over a lifetime – with reading simulated over decades – its performance now looked like that of an older adult. Often it was slower, but not because its processing capacity had declined. Rather, increased “experience” had caused the computer’s database to grow, giving it more data to process – which takes time.

Technology now allows researchers to make quantitative estimates of the number of words an adult can be expected to learn across a lifetime, enabling the Tübingen team to separate the challenge that increasing knowledge poses to memory from the actual performance of memory itself. “Imagine someone who knows two people’s birthdays and can recall them almost perfectly. Would you really want to say that person has a better memory than a person who knows the birthdays of 2000 people, but can ‘only’ match the right person to the right birthday nine times out of ten?” asks Ramscar.

The answer appears to be “no.” When Ramscar’s team trained their computer models on huge linguistic datasets, they found that standardized vocabulary tests, which are used to take account of the growth of knowledge in studies of ageing, massively underestimate the size of adult vocabularies. It takes computers longer to search databases of words as their sizes grow, which is hardly surprising but may have important implications for our understanding of age-related slowdowns. The researchers found that to get their computers to replicate human performance in word recognition tests across adulthood, they had to keep their capacities the same. “Forget about forgetting,” explained Tübingen researcher Peter Hendrix, “if I wanted to get the computer to look like an older adult, I had to keep all the words it learned in memory and let them compete for attention.”

The research shows that studies of the problems older people have with recalling names suffer from a similar blind spot: there is a far greater variety of given names today than there were two generations ago. This cultural shift toward greater name diversity means the number of different names anyone learns over their lifetime has increased dramatically. The work shows how this makes locating a name in memory far harder than it used to be. Even for computers.

Ramscar and his colleagues’ work provides more than an explanation of why, in the light of all the extra information they have to process, we might expect older brains to seem slower and more forgetful than younger brains. Their work also shows how changes in test performance that have been taken as evidence for declining cognitive abilities in fact demonstrates older adults’ greater mastery of the knowledge they have acquired.

Take “paired-associate learning,” a commonly used cognitive test that involves learning to connect words like “up” to “down” or “necktie” to “cracker” in memory. Using Big Data sets to quantify how often different words appear together in English, the Tuebingen team show that younger adults do better when asked to learn to pair “up” with “down” than “necktie” and “cracker” because “up” and “down” appear in close proximity to one another more frequently. However, whereas older adults also understand which words don’t usually go together, young adults notice this less. When the researchers examined performance on this test across a range of word pairs that go together more and less in English, they found older adult’s scores to be far more closely attuned to the actual information in hundreds of millions of words of English than their younger counterparts.

As Prof. Harald Baayen, who heads the Alexander von Humboldt Quantitative Linguistics research group where the work was carried out puts it, “If you think linguistic skill involves something like being able to choose one word given another, younger adults seem to do better in this task. But, of course, proper understanding of language involves more than this. You have also to not put plausible but wrong pairs of words together. The fact that older adults find nonsense pairs – but not connected pairs – harder to learn than young adults simply demonstrates older adults’ much better understanding of language. They have to make more of an effort to learn unrelated word pairs because, unlike the youngsters, they know a lot about which words don’t belong together.”

The Tübingen research conclude that we need different tests for the cognitive abilities of older people – taking into account the nature and amount of information our brains process. “The brains of older people do not get weak,” says Michael Ramscar. “On the contrary, they simply know more.”

Age no obstacle to nerve cell regeneration

In aging worms at least, it is insulin, not Father Time, that inhibits a motor neuron’s ability to repair itself — a finding that suggests declines in nervous system health may not be inevitable.

All organisms show a declining ability to regenerate damaged nervous systems with age, but the study appearing in the Feb. 5 issue of the journal Neuron suggests this deficit is not due to the ravages of time.

“The nervous system regulates its own response to age, separately from what happens in the rest of the body,” said Marc Hammarlund, assistant professor of genetics and senior author of the new study. “By manipulating the insulin pathway, we can make animals that live longer but have nervous systems that age normally, or conversely, we can make animals that die at a normal age but have a young nervous system.”

Alexandra Byrne, postdoctoral associate in genetics and lead author of the study, identified two genetic pathways that regulate insulin activity and are responsible for age-related declines in a worm’s ability to regenerate neuronal axons, or connective branches. The team pinpointed two other pathways that also regulate a neuron’s ability to regenerate, but that have no connection to the age of the worm.

The worm C. elegans is a well-established model to study the genetics of aging, and manipulation of the family of genes that regulate insulin activity has been shown to dramatically increase lifespan of the organism. The new study reveals that insulin signaling is also directly affecting the nervous system.

“We hope to understand how different pathways coordinately regulate neuronal aging, and more specifically, how to entice an aged neuron to regenerate after injury,” Byrne said.

“The hope is to increase healthspan, not just lifespan,” Hammarlund said.