Posts tagged dementia
Articles and news from the latest research reports.
Copper Identified as Culprit in Alzheimer’s Disease
Copper appears to be one of the main environmental factors that trigger the onset and enhance the progression of Alzheimer’s disease by preventing the clearance and accelerating the accumulation of toxic proteins in the brain. That is the conclusion of a study appearing today in the journal Proceedings of the National Academy of Sciences.
“It is clear that, over time, copper’s cumulative effect is to impair the systems by which amyloid beta is removed from the brain,” said Rashid Deane, Ph.D., a research professor in the University of Rochester Medical Center (URMC) Department of Neurosurgery, member of the Center for Translational Neuromedicine, and the lead author of the study. “This impairment is one of the key factors that cause the protein to accumulate in the brain and form the plaques that are the hallmark of Alzheimer’s disease.”
Copper’s presence in the food supply is ubiquitous. It is found in drinking water carried by copper pipes, nutritional supplements, and in certain foods such as red meats, shellfish, nuts, and many fruits and vegetables. The mineral plays an important and beneficial role in nerve conduction, bone growth, the formation of connective tissue, and hormone secretion.
However, the new study shows that copper can also accumulate in the brain and cause the blood brain barrier – the system that controls what enters and exits the brain – to break down, resulting in the toxic accumulation of the protein amyloid beta, a by-product of cellular activity. Using both mice and human brain cells Deane and his colleagues conducted a series of experiments that have pinpointed the molecular mechanisms by which copper accelerates the pathology of Alzheimer’s disease.
Under normal circumstances, amyloid beta is removed from the brain by a protein called lipoprotein receptor-related protein 1 (LRP1). These proteins – which line the capillaries that supply the brain with blood – bind with the amyloid beta found in the brain tissue and escort them into the blood vessels where they are removed from the brain.
The research team“dosed” normal mice with copper over a three month period. The exposure consisted of trace amounts of the metal in drinking water and was one-tenth of the water quality standards for copper established by the Environmental Protection Agency.
“These are very low levels of copper, equivalent to what people would consume in a normal diet.” said Deane.
The researchers found that the copper made its way into the blood system and accumulated in the vessels that feed blood to the brain, specifically in the cellular “walls” of the capillaries. These cells are a critical part of the brain’s defense system and help regulate the passage of molecules to and from brain tissue. In this instance, the capillary cells prevent the copper from entering the brain. However, over time the metal can accumulate in these cells with toxic effect.
The researchers observed that the copper disrupted the function of LRP1 through a process called oxidation which, in turn, inhibited the removal of amyloid beta from the brain. They observed this phenomenon in both mouse and human brain cells.
The researchers then looked at the impact of copper exposure on mouse models of Alzheimer’s disease. In these mice, the cells that form the blood brain barrier have broken down and become “leaky” – a likely combination of aging and the cumulative effect of toxic assaults – allowing elements such as copper to pass unimpeded into the brain tissue. They observed that the copper stimulated activity in neurons that increased the production of amyloid beta. The copper also interacted with amyloid beta in a manner that caused the proteins to bind together in larger complexes creating logjams of the protein that the brain’s waste disposal system cannot clear.
This one-two punch, inhibiting the clearance and stimulating the production of amyloid beta, provides strong evidence that copper is a key player in Alzheimer’s disease. In addition, the researchers observed that copper provoked inflammation of brain tissue which may further promote the breakdown of the blood brain barrier and the accumulation of Alzheimer’s-related toxins.
However, because metal is essential to so many other functions in the body, the researchers say that these results must be interpreted with caution.
“Copper is an essential metal and it is clear that these effects are due to exposure over a long period of time,” said Deane. “The key will be striking the right balance between too little and too much copper consumption. Right now we cannot say what the right level will be, but diet may ultimately play an important role in regulating this process.”
(Source: urmc.rochester.edu)
A Genetic Answer to the Alzheimer’s Riddle?
What if we could pinpoint a hereditary cause for Alzheimer’s, and intervene to reduce the risk of the disease? We may be closer to that goal, thanks to a team at the University of Kentucky. Researchers affiliated with the UK Sanders-Brown Center on Aging have completed new work in Alzheimer’s genetics; the research is detailed in a paper published today in the Journal of Neuroscience.
Emerging evidence indicates that, much like in the case of high cholesterol, some Alzheimer’s disease risk is inherited while the remainder is environmental. Family and twin studies suggest that about 70 percent of total Alzheimer’s risk is hereditary.
Recently published studies identified several variations in DNA sequence that each modify Alzheimer’s risk. In their work, the UK researchers investigated how one of these sequence variations may act. They found that a “protective” genetic variation near a gene called CD33 correlated strongly with how the CD33 mRNA was assembled in the human brain. The authors found that a form of CD33 that lacked a critical functional domain correlates with reduced risk of Alzheimers disease. CD33 is thought to inhibit clearance of amyloid beta, a hallmark of Alzheimers disease.
The results obtained by the UK scientists indicate that inhibiting CD33 may reduce Alzheimer’s risk. A drug tested for acute myeloid leukemia targets CD33, suggesting the potential for treatments based on CD33 to mitigate the risk for Alzheimer’s disease. Additional studies must be conducted before this treatment approach could be tested in humans.
Oprah’s and Einstein’s faces help spot dementia
New test designed for younger people reveals early-onset dementia
Simple tests that measure the ability to recognize and name famous people such as Albert Einstein, Bill Gates or Oprah Winfrey may help doctors identify early dementia in those 40 to 65 years of age, according to new Northwestern Medicine research.
The research appears in the August 13, 2013, print issue of Neurology, the medical journal of the American Academy of Neurology.
"These tests also differentiate between recognizing a face and actually naming it, which can help identify the specific type of cognitive impairment a person has," said study lead author Tamar Gefen, a doctoral candidate in neuropsychology at the Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University Feinberg School of Medicine.
Gefen did the research in the lab of senior author Emily Rogalski, assistant research professor at Northwestern’s Cognitive Neurology and Alzheimer’s Disease Center.
Face recognition tests exist to help identify dementia, but they are outdated and more suitable for an older generation.
"The famous faces for this study were specifically chosen for their relevance to individuals under age 65, so that the test may be useful for diagnosing dementia in younger individuals," Rogalski said. An important component of the test is that it distinguishes deficits in remembering the name of a famous person from that of recognizing the same individual, she noted.
The study also used quantitative software to analyze MRI scans of the brains of the individuals who completed the test to understand the brain areas important for naming and recognition of famous faces.
For the study, 30 people with primary progressive aphasia, a type of early onset dementia that mainly affects language, and 27 people without dementia, all an average age of 62, were given a test. The test includes 20 famous faces printed in black and white, including John F. Kennedy, Lucille Ball, Princess Diana, Martin Luther King Jr. and Elvis Presley.
Participants were given points for each face they could name. If the subject could not name the face, he or she was asked to identify the famous person through description. Participants gained more points by providing at least two relevant details about the person. The two groups also underwent MRI brain scans.
Researchers found that the people who had primary progressive aphasia, a form of early onset dementia, performed significantly worse on the test, scoring an average of 79 percent in recognition of famous faces and 46 percent in naming the faces, compared to 97 percent in recognition and 93 percent on naming for those free of dementia.
The study also found that people who had trouble putting names to the faces were more likely to have a loss of brain tissue in the left temporal lobe of the brain, while those with trouble recognizing the faces had tissue loss on both the left and right temporal lobe.
"In addition to its practical value in helping us identify people with early dementia, this test also may help us understand how the brain works to remember and retrieve its knowledge of words and objects," Gefen said.
High Blood Sugar Linked to Dementia
People with diabetes face an increased risk of Alzheimer’s disease and other forms of dementia, a connection scientists and physicians have worried about for years. They still can’t explain it.
Now comes a novel observational study of patients at a large health care system in Washington State showing that higher blood glucose levels are associated with a greater risk of dementia — even among people who don’t have diabetes. The results, published Thursday in The New England Journal of Medicine, “may have influence on the way we think about blood sugar and the brain,” said Dr. Paul Crane, the lead author and associate professor of medicine at the University of Washington.
The researchers tracked the blood glucose levels of 2,067 members of Group Health, a nonprofit HMO, for nearly seven years on average. Some patients had Type 2 diabetes when the study began, but most didn’t. None had dementia.
Over the years, as they saw doctors at Group Health, the participants received blood glucose tests. “It’s a common test in routine clinical practice,” Dr. Crane said. “We had an amazing opportunity with all this data. All the lab results since 1988 were available to us.”
The participants (average age at the start: 76) also reported to Group Health every other year for cognitive screening and, if their results were below normal, further testing and evaluation. Over the course of the study, about a quarter developed dementia of some kind, primarily Alzheimer’s disease or vascular dementia.
To measure blood sugar levels, the researchers combined glucose measurements, both fasting and nonfasting, with the HbA1c glycated hemoglobin assay, which provides a more accurate long-term picture. They also adjusted the data for other cardiovascular factors already linked to dementia, like high blood pressure and smoking.
“We found a steadily increasing risk associated with ever-higher blood glucose levels, even in people who didn’t have diabetes,” Dr. Crane said. Of particular interest: “There’s no threshold, no place where the risk doesn’t go up any further or down any further.” The association with dementia kept climbing with higher blood sugar levels and, at the other end of the spectrum, continued to decrease with lower levels.
This held true even at glucose levels considered normal. Among those whose blood sugar averaged 115 milligrams per deciliter, the risk of dementia was 18 percent higher than among those at 100 mg/dL, just slightly lower. The effects were also pronounced among those with diabetes: patients with average glucose levels of 190 mg/dL had a 40 percent higher risk of dementia than those whose levels averaged 160 mg/dL.
Though a longitudinal study like this one provides insight into the differences between people, it can’t explain why higher blood glucose might be connected to dementia, or tell individuals whether lower blood glucose is protective.
“People shouldn’t run for the hills or try crazy diets,” Dr. Crane cautioned. While an epidemiological study like this one can guide further exploration, he said, “This doesn’t show that changes in behavior that lower your individual blood sugar would decrease your individual risk of dementia.”
As for the blood glucose levels the study recorded, “clinically, they’re not big differences,” said Dr. Medha Munshi, a geriatrician and endocrinologist who directs the geriatric diabetes program at the Joslin Diabetes Center in Boston, who was not involved in the study. “I wouldn’t change my goals for diabetes management based on this study.” Nor would she warn someone whose blood glucose hits 115 mg/dL that he or she faces a greater risk of dementia.
But because diabetes itself can pose such a threat to health and quality of life, she still urges patients to adopt healthy practices like exercising regularly and maintaining a normal weight to try to avoid the disease. If by doing so they also lower their dementia risk — and knowing that would require a different study, focused on interventions — that would be a bonus.
This research “offers more evidence that the brain is a target organ for damage by high blood sugar,” said Dr. Munshi. “And everyone is still working on the ‘why’.
Breastfeeding may reduce Alzheimer’s risk
A new study suggests that mothers who breastfeed run a lower risk of developing Alzheimer’s, with longer periods of breastfeeding further reducing the risk.
Mothers who breastfeed their children may have a lower risk of developing Alzheimer’s Disease, with longer periods of breastfeeding also lowering the overall risk, a new study suggests.
The report, newly published in the Journal of Alzheimer’s Disease, suggests that the link may be to do with certain biological effects of breastfeeding. For example, breastfeeding restores insulin tolerance which is significantly reduced during pregnancy, and Alzheimer’s is characterised by insulin resistance in the brain.
Although they used data gathered from a very small group of just 81 British women, the researchers observed a highly significant and consistent correlation between breastfeeding and Alzheimer’s risk. They argue that this was so strong that any potential sampling error was unlikely.
At the same time, however, the connection was much less pronounced in women who already had a history of dementia in their family. The research team hope that the study – which was intended merely as a pilot – will stimulate further research looking at the relationship between female reproductive history and disease risk.
The findings may point towards new directions for fighting the global Alzheimer’s epidemic – especially in developing countries where cheap, preventative measures are desperately needed.
More broadly, the study opens up new lines of enquiry in understanding what makes someone susceptible to Alzheimer’s in the first place. It may also act as an incentive for women to breastfeed, rather than bottle-feed – something which is already known to have wider health benefits for both mother and child.
Dr Molly Fox, from the Department of Biological Anthropology at the University of Cambridge, who led the study, said: “Alzheimer’s is the world’s most common cognitive disorder and it already affects 35.6 million people. In the future, we expect it to spread most in low and middle-income countries. So it is vital that we develop low-cost, large-scale strategies to protect people against this devastating disease.”
Previous studies have already established that breastfeeding can reduce a mother’s risk of certain other diseases, and research has also shown that there may be a link between breastfeeding and a woman’s general cognitive decline later in life. Until now, however, little has been done to examine the impact of breastfeeding duration on Alzheimer’s risk.
Fox and her colleagues – Professor Carlo Berzuini and Professor Leslie Knapp – interviewed 81 British women aged between 70 and 100. These included both women with, and without, Alzheimer’s. In addition, the team also spoke to relatives, spouses and carers.
Through these interviews, the researchers collected information about the women’s reproductive history, their breastfeeding history, and their dementia status. They also gathered information about other factors that might account for their dementia, for example, a past stroke, or brain tumour.
Dementia status itself was measured using a standard rating scale called the Clinical Dementia Rating (CDR). The researchers also developed a method for estimating the age of Alzheimer’s sufferers at the onset of their disease, using the CDR as a basis and taking into account their age and existing, known patterns of Alzheimer’s progression. All of this information was then compared with the participants’ breastfeeding history.
Despite the small number of participants, the study revealed a number of clear links between breastfeeding and Alzheimer’s. These were not affected when the researchers took into account other potential variables such as age, education history, the age when the woman first gave birth, her age at menopause, or her smoking and drinking history.
The researchers observed three main trends:
- Women who breastfed exhibited a reduced Alzheimer’s Disease risk compared with women who did not.
- Longer breastfeeding history was significantly associated with a lower Alzheimer’s Risk.
- Women who had a higher ratio of total months pregnant during their life to total months breastfeeding had a higher Alzheimer’s risk.
The trends were, however, far less pronounced for women who had a parent or sibling with dementia. In these cases, the impact of breastfeeding on Alzheimer’s risk appeared to be significantly lower, compared with women whose families had no history of dementia.
The study argues that there may be a number of biological reasons for the connection between Alzheimer’s and breastfeeding, all of which require further investigation.
One theory is that breastfeeding deprives the body of the hormone progesterone, compensating for high levels of progesterone which are produced during pregnancy. Progesterone is known to desensitize the brain’s oestrogen receptors, and oestrogen may play a role in protecting the brain against Alzheimer’s.
Another possibility is that breastfeeding increases a woman’s glucose tolerance by restoring her insulin sensitivity after pregnancy. Pregnancy itself induces a natural state of insulin resistance. This is significant because Alzheimer’s is characterised by a resistance to insulin in the brain (and therefore glucose intolerance) to the extent that it is even sometimes referred to as “Type 3 diabetes”.
“Women who spent more time pregnant without a compensatory phase of breastfeeding therefore may have more impaired glucose tolerance, which is consistent with our observation that those women have an increased risk of Alzheimer’s disease,” Fox added.
New drugs to find the right target to fight Alzheimer’s disease
Next-generation drugs designed to fight Alzheimer’s disease look very promising. Scientists have unveiled the mechanisms behind two classes of compound currently being tested in clinical trials. They have also identified a likely cause of early-onset hereditary forms of the disease.
The future is looking good for drugs designed to combat Alzheimer’s disease. EPFL scientists have unveiled how two classes of drug compounds currently in clinical trials work to fight the disease. Their research suggests that these compounds target the disease-causing peptides with high precision and with minimal side-effects. At the same time, the scientists offer a molecular explanation for early-onset hereditary forms of Alzheimer’s, which can strike as early as thirty years of age. The conclusions of their research, which has been published in the journal Nature Communications, are very encouraging regarding the future of therapeutic means that could keep Alzheimer’s disease in check.
Alzheimer’s disease is characterized by an aggregation of small biological molecules known as amyloid peptides. We all produce these molecules; they play an essential antioxidant role. But in people with Alzheimer’s disease, these peptides aggregate in the brain into toxic plaques – called “amyloid plaques” – that destroy the surrounding neurons.
The process starts with a long protein, “APP”, which is located across the neuron’s membrane. This protein is cut into several pieces by an enzyme, much like a ribbon is cut by scissors. The initial cut generates a smaller intracellular protein that plays a useful role in the neuron. Another cut releases the rest of APP outside the cell – this part is the amyloid peptide.
For reasons not yet well understood, APP protein can be cut in several different places, producing amyloid peptides that are of varying lengths. Only the longer forms of the amyloid peptide carry the risk of aggregating into plaques, and people with Alzheimer’s disease produce an abnormally high number of these.
A favorite Alzheimer’s target: gamma secretase
The two next-generation classes of compound that are currently in clinical trials target an enzyme that cuts APP, known as gamma secretase. Until now, our understanding of the mechanism involved has been lacking. But with this work, the EPFL researchers were able to shed some more light on it by determining how the drug compounds affect gamma secretase and its cutting activity.
In most forms of Alzheimer’s, abnormally large quantities of the long amyloid peptide 42 – named like that because it contains 42 amino acids – are formed. The drug compounds change the location where gamma secretase cuts the APP protein, thus producing amyloid peptide 38 instead of 42, which is shorter and does not aggregate into neurotoxic plaques.
Compared to previous therapeutic efforts, this is considerable progress. In 2010, Phase III clinical trials had to be abandoned, because the compound being tested inhibited gamma-secretase’s function across the board, meaning that the enzyme was also deactivated in essential cellular differentiation processes, resulting to side-effects like in gastrointestinal bleeding and skin cancer.
“Scientists have been trying to target gamma secretase to treat Alzheimer’s for over a decade,” explains Patrick Fraering, senior author on the study and Merck Serono Chair of Neurosciences at EPFL. “Our work suggests that next-generation molecules, by modulating rather than inhibiting the enzyme, could have few, if any, side-effects. It is tremendously encouraging.”
New insights into hereditary forms of the disease
During their investigation, the scientists also identified possible causes behind some hereditary forms of Alzheimer’s disease. Early-onset Alzheimer’s can appear as early as thirty years of age, with a life expectancy of only a few years. In vitro experiments and numerical simulations show that in early-onset patients, mutations in the APP protein gene modify the way by which APP is cut by the gamma-secretase enzyme. This results in overproduction of amyloid peptide 42, which then aggregates into amyloid plaques.
This research illuminates much that is unknown about Alzheimer’s disease. “We have obtained extraordinary knowledge about how gamma secretase can be modulated,” explains co-author Dirk Beher, scientific chief officer of Asceneuron, a spin-off of Merck Serono, the biopharmaceutical division of Merck KGaA, Darmstadt, Germany. “This knowledge will be invaluable for developing even better targeted drugs to fight the disease.”
(Source: actu.epfl.ch)
Anemia Linked to Increased Risk of Dementia
Anemia, or low levels of red blood cells, may increase the risk of dementia, according to a study published in the July 31, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“Anemia is common in the elderly and occurs in up to 23 percent of adults ages 65 and older,” said study author Kristine Yaffe, MD, with the University of California – San Francisco and a member of the American Academy of Neurology. “The condition has also been linked in studies to an increased risk of early death.”
For the study, 2,552 older adults between the ages of 70-79 were tested for anemia and also underwent memory and thinking tests over 11 years. Of those, 393 had anemia at the start of the study. At the end of the study, 445, or about 18 percent of participants, developed dementia.
The research found that people who had anemia at the start of the study had a nearly 41 percent higher risk of developing dementia than those who were not anemic. The link remained after considering other factors, such as age, race, sex and education. Of the 393 people with anemia, 89 people, or 23 percent, developed dementia, compared to 366 of the 2,159 people who did not have anemia, or 17 percent.
“There are several explanations for why anemia may be linked to dementia. For example, anemia may be a marker for poor health in general, or low oxygen levels resulting from anemia may play a role in the connection. Reductions in oxygen to the brain have been shown to reduce memory and thinking abilities and may contribute to damage to neurons,” said Yaffe.
A possible blood test for Alzheimer’s disease?
A new blood test can be used to discriminate between people with Alzheimer’s disease and healthy controls. It’s hoped the test, described in the open access journal Genome Biology, could one day be used to help diagnose the disease and other degenerative disorders.
Alzheimer’s disease, the most common form of dementia, can only be diagnosed with certainty at autopsy, so the hunt is on to find reliable, non-invasive biomarkers for diagnosis in the living. Andreas Keller and colleagues focused on microRNAs (miRNAs), small non-coding RNA molecules known to influence the way genes are expressed, and which can be found circulating in bodily fluids including blood.
The team, from Saarland University and Siemens Healthcare highlighted and tested a panel of 12 miRNAs, levels of which were found to be different amongst a small sample of Alzheimer’s patients and healthy controls. In a much bigger sample, the test reliably distinguished between the two groups.
Decent biomarkers need to be accurate, sensitive (able to correctly identify people with the disease) and specific (able to correctly pinpoint people without the disease). The new test scores over 90% on all three measures. But whilst the test shows obvious promise, it still needs to be validated for clinical use, and may eventually work best when combined with other standard diagnostic tools, such as imaging, the authors say.
As people with other brain disorders can sometimes show Alzheimer’s-like symptoms, the team also looked for the miRNA signature in other patient groups. The test distinguished controls from people with various psychological disorders, such as schizophrenia and depression, with over 95% accuracy, and from patients with other neurodegenerative disorders, such as mild cognitive impairment and Parkinson’s disease, with lower accuracy. It also discriminated between Alzheimer’s patients and patients with other neurodegenerative disorders, with an accuracy of around 75%. But by tweaking the miRNAs used in the test, accuracy could be improved.
The work builds on previous studies highlighting the potential of miRNAs as blood-based biomarkers for many diseases, including numerous cancers, and suggests that miRNAs could yield useful biomarkers for various brain disorders. But it also sheds light on the mechanisms underpinning Alzheimer’s disease. Two of the miRNAs are known involved in amyloid precursor protein processing, which itself is involved in the formation of plaques, a classic hallmark of Alzheimer’s disease. And many of the miRNAs are believed to influence the growth and shape of neurons in the developing brain.
(Image: Reuters)
Certain blood pressure drugs slow dementia deterioration
A class of drug, called ACE inhibitors, which are used to lower blood pressure, slow the rate of cognitive decline typical of dementia, suggests research published in the online journal BMJ Open.
Furthermore, these drugs may even boost brain power, the research indicates.
The researchers compared the rates of cognitive decline in 361 patients who had either been diagnosed with Alzheimer’s disease, vascular dementia, or a mix of both.
Eighty five of the patients were already taking ACE inhibitors; the rest were not.
The researchers also assessed the impact of ACE inhibitors on the brain power of 30 patients newly prescribed these drugs, during their first six months of treatment. The average age of all the participants was 77.
Between 1999 and 2010, the cognitive decline of each patient was assessed using either the Standardised Mini Mental State Examination (SMMSE) or the Quick Mild Cognitive Impairment (Qmci) screen on two separate occasions, six months apart.
Compared with those not taking ACE inhibitors, those on these drugs experienced marginally slower rates of cognitive decline.
In those whose brain power had been assessed by Qmci, which is a more sensitive screen than the SMMSE, the difference was small, but significant.
And the brain power of those patients newly prescribed ACE inhibitors actually improved over the six month period, compared with those already taking them, and those not taking them at all.
This might be because these patients stuck to their medication regimen better, or it might be a by-product of better blood pressure control, or improved blood flow to the brain, suggest the authors.
But it is the first time that there has been any evidence to suggest that blood pressure lowering drugs may not only halt cognitive decline, but may actually improve brain power.
“This [study] supports the growing body of evidence for the use of ACE inhibitors and other [blood pressure lowering] agents in the management of dementia,” write the authors.
“Although the differences were small and of uncertain clinical significance, if sustained over years, the compounding effects may well have significant clinical benefits,” they add.
They caution, however, that recent evidence indicates that ACE inhibitors may be harmful in some cases, so if larger studies confirm that they work well in dementia, it may be only certain groups of patients with the condition who stand to benefit.
(Source: group.bmj.com)
New clues illuminate Alzheimer’s roots
Scientists at Rice University and the University of Miami have figured out how synthetic molecules designed at Rice latch onto the amyloid peptide fibrils thought to be responsible for Alzheimer’s disease. Their discovery could point the way toward therapies to halt or even reverse the insidious disease.
The metallic dipyridophenazine ruthenium molecules strongly bind to pockets created when fibrils form from misfolded proteins that cells fail to destroy. When excited under a spectroscope, the molecules luminesce, which indicates the presence of the fibrils. That much was known by Rice researchers, but until now the process was a mystery.
By combining their talents in biophysics (at Rice) and computer simulation (at Miami), researchers pinpointed four such pockets along the fibril where the hydrophobic (water-averse) molecules can bind. They believe their work will help chemists design molecules to keep the fibrils from forming the plaques found in Alzheimer’s patients.
The teams led by Rice chemist Angel Martí and Miami chemist Rajeev Prabhakar reported their results in the Journal of the American Chemical Society this month.
Two years ago, Martí and Nathan Cook, a graduate student in his lab and lead author of the new paper, combined ruthenium complexes with solutions containing the spaghetti-like amyloid fibrils. The complexes don’t luminesce by themselves, but when they link to an amyloid fibril, they can be triggered by light at one wavelength to glow at another; this helps the researchers “see” the fibrils.
This ability to track amyloids was a great step forward, but left open the question of why the complexes latched onto the fibrils at all, Cook said.
“We had no way to figure it out because our experimental techniques can’t identify binding sites,” he said. “The standard (used to analyze proteins) is to crystallize your material and use X-rays to determine where everything is positioned. The problem with amyloid beta is the fibrils are not uniform, and you can’t crystallize them. All you would get is an amorphous lump.”
But a door opened when Prabhakar, a theoretical and computational chemist who specializes in amyloids, contacted Martí and suggested a collaboration. “We both knew the other was working with amyloid betas,” Martí said. “We were able to figure out how many amyloid beta monomers (molecules that can bind with each other) had to come together to form fibrils, while he modeled the interactions. When we brought all the data together, we had a perfect match.”
“Basically, we learned from the model that we need two monomers to form a binding site,” Marti said. “The cleft where the ruthenium complex binds is completely hydrophobic, the same as the complex. Neither wants to be exposed to water, so when they find each other, they don’t have a choice but to come together. It turns out that’s exactly what needs to happen to turn on the photoluminescent response of the compound.”
Martí said testing various concentrations of monomers with ruthenium complexes helped them determine that a little more than two monomers, on average, was sufficient to get the “light switch” effect. Prabhakar’s analysis found four specific locations along the aggregating monomers where the ruthenium complexes could bind: two at the ends where the monomers tend to bind to each other, and two in the middle.
“It was a complicated system to model and we tried hard, using a variety of computational techniques,” Prabhakar said. “In the end, we were amazed to find our results in perfect agreement with the experiments performed in the Martí lab.”
The researchers called the end locations “A and B,” and the middle clefts “C and D.” The hydrophobic A and B sites exist only at the edges of the fibrils, which limits their exposure to the complexes, Martí said. “But there are lots of C and D sites,” he said. “That explains why the ruthenium complexes don’t inhibit the aggregation of fibrils. It seems the system prefers to bind another monomer, rather than a ruthenium complex, at the ends.
“But now that we understand the mechanism, we can design more hydrophobic complexes that could bind strongly to the ends and prevent further elongation of the fibril,” he said.
“There’s a whole variety of ways to tweak this that could potentially disrupt a binding pocket,” Cook said.
More challenges lie beyond the new discovery, he said. New research indicates toxic oligomers may be catalyzed by the formation of amyloid fibrils. “We might be able to prevent the formation of these oligomeric species by binding ruthenium complexes to the surface, which would completely change the surface chemistry of the fibrils,” Martí said. “These are the things we are really interested in doing right now.”