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.”

Blood Test Identifies Those At-Risk for Cognitive Decline, Alzheimer’s Within 3 Years

Researchers have discovered and validated a blood test that can predict with greater than 90 percent accuracy if a healthy person will develop mild cognitive impairment or Alzheimer’s disease within three years.

Described in the April issue of Nature Medicine, the study heralds the potential for developing treatment strategies for Alzheimer’s at an earlier stage, when therapy would be more effective at slowing or preventing onset of symptoms. It is the first known published report of blood-based biomarkers for preclinical Alzheimer’s.

The test identifies 10 lipids, or fats, in the blood that predict disease onset. It could be ready for use in clinical studies in as few as two years and, researchers say, other diagnostic uses are possible.

“Our novel blood test offers the potential to identify people at risk for progressive cognitive decline and can change how patients, their families and treating physicians plan for and manage the disorder,” says the study’s corresponding author Howard J. Federoff, MD, PhD, professor of neurology and executive vice president for health sciences at Georgetown University Medical Center.

There is no cure or effective treatment for Alzheimer’s. Worldwide, about 35.6 million individuals have the disease and, according to the World Health Organization, the number will double every 20 years to 115.4 million people with Alzheimer’s by 2050.

Federoff explains there have been many efforts to develop drugs to slow or reverse the progression of Alzheimer’s disease, but all of them have failed. He says one reason may be the drugs were evaluated too late in the disease process.

“The preclinical state of the disease offers a window of opportunity for timely disease-modifying intervention,” Federoff says. “Biomarkers such as ours that define this asymptomatic period are critical for successful development and application of these therapeutics.”

The study included 525 healthy participants aged 70 and older who gave blood samples upon enrolling and at various points in the study. Over the course of the five-year study, 74 participants met the criteria for either mild Alzheimer’s disease (AD) or a condition known as amnestic mild cognitive impairment (aMCI), in which memory loss is prominent. Of these, 46 were diagnosed upon enrollment and 28 developed aMCI or mild AD during the study (the latter group called converters).

In the study’s third year, the researchers selected 53 participants who developed aMCI/AD (including 18 converters) and 53 cognitively normal matched controls for the lipid biomarker discovery phase of the study. The lipids were not targeted before the start of the study, but rather, were an outcome of the study.

A panel of 10 lipids was discovered, which researchers say appears to reveal the breakdown of neural cell membranes in participants who develop symptoms of cognitive impairment or AD. The panel was subsequently validated using the remaining 21 aMCI/AD participants (including 10 converters), and 20 controls. Blinded data were analyzed to determine if the subjects could be characterized into the correct diagnostic categories based solely on the 10 lipids identified in the discovery phase.

“The lipid panel was able to distinguish with 90 percent accuracy these two distinct groups: cognitively normal participants who would progress to MCI or AD within two to three years, and those who would remain normal in the near future,” Federoff says.

The researchers examined if the presence of the APOE4 gene, a known risk factor for developing AD, would contribute to accurate classification of the groups, but found it was not a significant predictive factor in this study.

“We consider our results a major step toward the commercialization of a preclinical disease biomarker test that could be useful for large-scale screening to identify at-risk individuals,” Federoff says. “We’re designing a clinical trial where we’ll use this panel to identify people at high risk for Alzheimer’s to test a therapeutic agent that might delay or prevent the emergence of the disease.”

Protein reelin rescues cognitive impairment in animal models of Alzheimer’s disease

The scientists Eduardo Soriano and Lluís Pujadas, from the University of Barcelona (UB), and the “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas” (CIBERNED) have led research into the role of reelin in animal models of Alzheimer’s disease.

Published today in the journal Nature Communications, the study demonstrates how an increase in the levels of reelin—a protein that is essential for cerebral cortex plasticity—has the capacity to restore cognitive capacity in mouse models of Alzheimer’s disease, delaying amyloid-beta (Αβ) fibril formation in vitro and reducing the accumulation of amyloid deposits in the brains of animals affected by this disease.

The study, which was started four years ago, has involved the collaboration of members of the Peptides and Proteins lab at the Institute for Research in Biomedicine (IRB), namely Bernat Serra-Vidal, PhD student, Ernest Giralt, group leader, and Natàlia Carulla, associate researcher whose investigation focuses on the aggregation of Αβ. Alzheimer’s disease, which affects approximately 500,000 people in Spain, is characterised by the loss of neural connections and by neuronal death, both associated mainly with the formation of senile plaques (extracellular deposits of Aβ) and the presence of neurofibrillary tangles (intracellular deposits of tau protein.

In the IRB lab, researchers have performed experiments in vitro to determine whether there is an interaction between Aβ aggregation and reelin. These assays have revealed that reelin interacts with the Aβ peptide, delaying the formation of Aβ fibrils until it is trapped within them. “When reelins becomes trapped in Aβ fibrils, it loses its capacity to strengthen synaptic plasticity. This explains why an increase in reelin expression in the brain may be beneficial,” explain the authors of the study.

The hypotheses from the work in vitro have been tested in vivo using experimental animals. This study is the first to demonstrate a neuroprotective effect of reelin in neurodegenerative disease and, in addition, offers a possible explanation for this protective role.

Inherited Alzheimer’s damage greater decades before symptoms appear

In a paper published in the prestigious journal Science Translational Medicine, Professor Colin Masters from the Florey Institute of Neuroscience and Mental Health and University of Melbourne – and colleagues in the UK and US – have found rapid neuronal damage begins 10 to 20 years before symptoms appear.

“As part of this research we have observed other changes in the brain that occur when symptoms begin to appear. There is actually a slowing of the neurodegeneration,” said Professor Masters.
Autosomal-dominant Alzheimer’s affects families with a genetic mutation, predisposing them to the crippling disease. These families provide crucial insight into the development of Alzheimer’s because they can be identified years before symptoms develop. The information gleaned from this group will also influence treatment offered to those living with the more common age-related version. Only about one per cent of those with Alzheimer’s have the genetic type of the disease.

The next part of the study involves a clinical trial. Using a range of imaging techniques (MRI and PET) and analysis of blood and cerebrospinal fluid, individuals from the US, UK and Australia will be observed as they trial new drugs to test their safety, side effects and changes within the brain.

 “As part of an international study, family members are invited to be part of a trial in which two experimental drugs are offered many years before symptoms appear,” Prof Masters says. “It’s going to be very interesting to see how clinical intervention affects this group of patients in the decades before symptoms appear.”

The Florey is looking to recruit more participants in the Dominantly Inherited Alzheimer Network (DIAN) study. Those who either know they have a genetic mutation that causes autosomal-dominant Alzheimer’s or who don’t know their genetic status but have a parent or sibling with the mutation are invited to email: dian@florey.edu.au

Yeast model reveals Alzheimer’s drug candidate and its mechanism of action

Using a yeast model of Alzheimer’s disease (AD), Whitehead Institute researchers have identified a drug that reduces levels of the toxic protein fragment amyloid-β (Aβ) and prevents at least some of the cellular damage caused when Ab accumulates in the brains of AD patients.

“We can use this yeast model to find small molecules that will address the underlying cellular pathologies of Alzheimer’s, an age-related disease whose burden will become even more significant as our population grows older,” says Kent Matlack, a former staff scientist in Whitehead Member Susan Lindquist’s lab. “We need a no-holds-barred approach to find effective compounds, and we need information about their mechanism of action quickly. Our work demonstrates that using a yeast model of Ab toxicity is a valid way to do this.”

The U.S. National Institute on Aging estimates that 5.1 million Americans may have AD, the most common form of dementia, which progressively robs patients of their memories, thinking, and reasoning skills. Research focused on the disease has been hampered by the affected cells’ location in the brain, where they cannot be studied until after an AD patient’s death. To explore the cellular processes compromised by AD, researchers in Lindquist’s lab created a yeast model, first described in the journal Science in 2011, that mimics in vivo the accumulation of Aβ that occurs in the human disease.

In the current research, which is described in this week’s issue of the journal Proceedings of the National Academy of Sciences (PNAS), a team of scientists in Lindquist’s lab used the yeast model to screen approximately 140,000 compounds to identify those capable of rescuing the cells from Aβ toxicity. One of the more promising classes of compounds has previously shown efficacy in animal models of AD and is about to complete a second phase II trial for AD. The mechanism by which the best-studied member of this class, clioquinol, targets Ab within the cell – where a large portion of it is produced in neurons – was unclear.  

“Our work in the yeast model shows that clioquinol decreases the amount of Aβ in the cells by 90%,” says Daniel Tardiff, a scientist in Lindquist’s lab. “That’s a strong decrease, and it’s dose-dependent. I’ve tested a lot of compounds before, and I’ve never seen anything as dramatic.”

Clioquinol chelates copper, meaning that it selectively binds the metal. In many AD patients, Aβ aggregates have higher concentrations of copper and other metals than normal, healthy brain tissue. Biochemical experiments also show that copper makes Aβ more toxic.

With clioquinol’s chelation capabilities in mind, Tardiff and Matlack, co-authors of the PNAS paper, tested clioquinol’s effect on Aβ-expressing cells in the presence of copper. The drug dramatically increased the degradation of Aβ in a copper-dependent manner, and even restored the cellular protein-trafficking process known as endocytosis, which is disrupted in both the yeast model and in AD-affected neurons.

“The clioquinol probably has a slightly higher affinity for copper than Aβ does, but it is not a strong enough chelator to strip the cell’s normal metalloproteins of the copper they need,” says Matlack. “From what we’ve seen in the yeast model, we think the drug pulls the copper away from Aβ. That would alter Aβ’s structure and likely make it more susceptible to degradation, thus shortening its half-life in the cell.”

The results from clioquinol in yeast and the clinical potential of closely related compounds are promising. While these compounds are not yet ready to serve as AD drugs in the clinic, the identification of an AD-relevant compound and cellular pathology – along with the Lindquist lab’s previous identification of human AD risk alleles that reduce Ab toxicity in yeast – suggests that this discovery platform will continue to yield information and lead to more compounds with equal or greater effectiveness, some of which will hopefully make a difference in human disease.

“It is important to remember that this class of compounds was shown to work in mouse models and in a limited human trial,” says Lindqust, who is also a professor of biology at MIT and an investigator of the Howard Hughes Medical Institute. “We have validated the yeast model and shown that we can find such compounds at a speed that was inconceivable before—indeed we found some compounds that look even more effective.”

Scientists wake up to causes of sleep disruption in Alzheimer’s disease

Being awake at night and dozing during the day can be a distressing early symptom of Alzheimer’s disease, but how the disease disrupts our biological clocks to cause these symptoms has remained elusive.

Now, scientists from Cambridge have discovered that in fruit flies with Alzheimer’s the biological clock is still ticking but has become uncoupled from the sleep-wake cycle it usually regulates. The findings – published in Disease Models & Mechanisms – could help develop more effective ways to improve sleep patterns in people with the disease.

People with Alzheimer’s often have poor biological rhythms, something that is a burden for both patients and their carers. Periods of sleep become shorter and more fragmented, resulting in periods of wakefulness at night and snoozing during the day. They can also become restless and agitated in the late afternoon and early evening, something known as ‘sundowning’.

Biological clocks go hand in hand with life, and are found in everything from single celled organisms to fruit flies and humans. They are vital because they allow organisms to synchronise their biology to the day-night changes in their environments.

Until now, however, it has been unclear how Alzheimer’s disrupts the biological clock. According to Dr Damian Crowther of Cambridge’s Department of Genetics, one of the study’s authors: “We wanted to know whether people with Alzheimer’s disease have a poor behavioural rhythm because they have a clock that’s stopped ticking or they have stopped responding to the clock.”

The team worked with fruit flies – a key species for studying Alzheimer’s. Evidence suggests that the A-beta peptide, a protein, is behind at least the initial stages of the disease in humans. This has been replicated in fruit flies by introducing the human gene that produces this peptide.

Taking a group of healthy flies and a group with this feature of Alzheimer’s, the researchers studied sleep-wake patterns in the flies, and how well their biological clocks were working.

They measured sleep-wake patterns by fitting a small infrared beam, similar to movement sensors in burglar alarms, to the glass tubes housing the flies. When the flies were awake and moving, they broke the beam and these breaks in the beam were counted and recorded.

To study the flies’ biological clocks, the researchers attached the protein luciferase – an enzyme that emits light – to one of the proteins that forms part of the biological clock. Levels of the protein rise and fall during the night and day, and the glowing protein provided a way of tracing the flies’ internal clock.

"This lets us see the brain glowing brighter at night and less during the day, and that’s the biological clock shown as a glowing brain. It’s beautiful to be able to study first hand in the same organism the molecular working of the clock and the corresponding behaviours," Dr Crowther said.

They found that healthy flies were active during the day and slept at night, whereas those with Alzheimer’s sleep and wake randomly. Crucially, however, the diurnal patterns of the luciferase-tagged protein were the same in both healthy and diseased flies, showing that the biological clock still ticks in flies with Alzheimer’s.

"Until now, the prevailing view was that Alzheimer’s destroyed the biological clock," said Crowther.

"What we have shown in flies with Alzheimer’s is that the clock is still ticking but is being ignored by other parts of the brain and body that govern behaviour. If we can understand this, it could help us develop new therapies to tackle sleep disturbances in people with Alzheimer’s."

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, who helped to fund the study, said: “Understanding the biology behind distressing symptoms like sleep problems is important to guide the development of new approaches to manage or treat them. This study sheds more light on the how features of Alzheimer’s can affect the molecular mechanisms controlling sleep-wake cycles in flies.

"We hope these results can guide further studies in people to ensure that progress is made for the half a million people in the UK with the disease."

After death, twin brains show similar patterns of neuropathologic changes

Despite widespread use of a single term, Alzheimer’s disease is actually a diverse collection of diseases, symptoms and pathological changes. What’s happening in the brain often varies widely from patient to patient, and a trigger for one person may be harmless is another.

In a unique study, an international team of researchers led by USC psychologist Margaret Gatz compared the brains of twins where one or both died of Alzheimer’s disease. They found that many of the twin pairs not only had similar progressions of Alzheimer’s disease and dementia prior to death, but they also had similar combinations of pathologies — two-or-more unconnected areas of damage to the brain.

The paper is part of Gatz’s landmark body of work on aging and cognition with the Swedish Twin Registry, a large cohort study of more than 14,000 Swedish twins, now over the age of 65. Across nearly 30 years, Gatz’s work with twins — including genetically identical pairs — has shifted the study of Alzheimer’s disease to include the entire lifespan, including the effects of developmental exposure, periodontal disease, mental health, obesity and diabetes on later-life Alzheimer’s risk.

The current paper provides more evidence that there may not be a single smoking-gun cause of Alzheimer’s, but rather a range of potential causes to which we may be susceptible largely depending on our genetics. It appears in the current issue of the journal Brain Pathology.

“We try to make inferences based on tests and diagnoses, but we have to assume that what we’re seeing is a manifestation of what’s going on in these twins’ brains,” said Gatz, professor of psychology, gerontology and preventive medicine in USC Dornsife College. “For this reason, we wanted to compare the brains of twins to ask whether identical twins’ brains are actually more identical?”

The researchers had the rare opportunity to directly autopsy the brains of seven pairs of twins who both died after being receiving diagnostic evaluations over many years, including a pair of identical twins who were both diagnosed with Alzheimer’s and died within a year of one another at the age of 98.

“There may be risk factors that start to accumulate but don’t lead to a clinical diagnosis,” explained lead author Diego Iacono of the Karolinska Institute in Sweden and the Biomedical Research Institute. “We found that the presence of Alzheimer’s disease doesn’t preclude the presence of other damage. Looking at co-pathologies in twin pairs may present new areas for research aside from the typical factors.”

For example, while there’s wide consensus among experts about the course of Alzheimer’s disease and the presence of amyloid plaques and tangles in the brain, what starts the process going is less clear, including the role of lesions, Lewy bodies and vascular or ventricle damage, more often associated with specific types of dementia such as Parkinson’s disease.

“Identical twins tended to have similar combinations of pathologies. We looked not just at the hallmark indicators of Alzheimer’s, but at all the other damage in the brain. Across the whole array of neuropathological changes, the identical twins appeared to have more similar pathologies,” Gatz said. “This is fascinating: it’s not just a key pathology related to the twins’ diagnoses but the combination of things happening in their brains. We’re going to keep looking for what these combinations are.”

(Image: Getty)

An Amazing Village Designed Just For People With Dementia

Centuries after Shakespeare wrote about King Lear’s symptoms, there’s still no perfect way to care for sufferers of dementia and Alzheimer’s. In the Netherlands, however, a radical idea is being tested: Self-contained “villages” where people with dementia shop, cook, and live together—safely.

We, as a population, are aging rapidly. According to the Alzheimer’s Association, one in three seniors today dies with dementia. The process of finding—and paying for—long-term care can be very confusing, unfortunately, and difficult for both loved ones and patients. Most caretakers are underpaid, overworked, and must drive far distances to their jobs—giving away some 17 billion unpaid hours of care a year. And it’s just going to get worse: Alzheimer’s has increased by an incredible 68 percent since 2000, and the cost of caring for sufferers will increase from $203 billion last year to $1.2 trillion by 2050.

In short, we’re not prepared for the future that awaits us—financially, infrastructurally, or even socially. But in the small town of Weesp, in Holland—that bastion of social progressivism—at a dementia-focused living center called De Hogeweyk, aka Dementiavillage, the relationship between patients and their care is serving as a model for the rest of the world.

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