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.

Exercise May be the Best Medicine for Alzheimer’s

New research out of the University of Maryland School of Public Health shows that exercise may improve cognitive function in those at risk for Alzheimer’s by improving the efficiency of brain activity associated with memory. Memory loss leading to Alzheimer’s disease is one of the greatest fears among older Americans. While some memory loss is normal and to be expected as we age, a diagnosis of mild cognitive impairment, or MCI, signals more substantial memory loss and a greater risk for Alzheimer’s, for which there currently is no cure.

The study, led by Dr. J. Carson Smith, assistant professor in the Department of Kinesiology, provides new hope for those diagnosed with MCI. It is the first to show that an exercise intervention with older adults with mild cognitive impairment (average age 78) improved not only memory recall, but also brain function, as measured by functional neuroimaging (via fMRI). The findings are published in the Journal of Alzheimer’s Disease.

“We found that after 12 weeks of being on a moderate exercise program, study participants improved their neural efficiency – basically they were using fewer neural resources to perform the same memory task,” says Dr. Smith. “No study has shown that a drug can do what we showed is possible with exercise.”

Recommended Daily Activity: Good for the Body, Good for the Brain
Two groups of physically inactive older adults (ranging from 60-88 years old) were put on a 12-week exercise program that focused on regular treadmill walking and was guided by a personal trainer.  Both groups – one which included adults with MCI and the other with healthy brain function – improved their cardiovascular fitness by about ten percent at the end of the intervention. More notably, both groups also improved their memory performance and showed enhanced neural efficiency while engaged in memory retrieval tasks.

The good news is that these results were achieved with a dose of exercise consistent with the physical activity recommendations for older adults. These guidelines urge moderate intensity exercise (activity that increases your heart rate and makes you sweat, but isn’t so strenuous that you can’t hold a conversation while doing it) on most days for a weekly total of 150 minutes.

Measuring Exercise’s Impact on Brain Health and Memory
One of the first observable symptoms of Alzheimer’s disease is the inability to remember familiar names. Smith and colleagues had study participants identify famous names and measured their brain activation while engaged in correctly recognizing a name – e.g., Frank Sinatra, or other celebrities well known to adults born in the 1930s and 40s. “The task gives us the ability to see what is going on in the brain when there is a correct memory performance,” Smith explains.

Tests and imaging were performed both before and after the 12-week exercise intervention. Brain scans taken after the exercise intervention showed a significant decrease in the intensity of brain activation in eleven brain regions while participants correctly identified famous names. The brain regions with improved efficiency corresponded to those involved in the pathology of Alzheimer’s disease, including the precuneus region, the temporal lobe, and the parahippocampal gyrus.

The exercise intervention was also effective in improving word recall via a “list learning task,” i.e., when people were read a list of 15 words and asked to remember and repeat as many words as possible on five consecutive attempts, and again after a distraction of being given another list of words.

“People with MCI are on a very sharp decline in their memory function, so being able to improve their recall is a very big step in the right direction,” Smith states.

The results of Smith’s study suggest that exercise may reduce the need for over-activation of the brain to correctly remember something. That is encouraging news for those who are looking for something they can do to help preserve brain function.

Dr. Smith has plans for a larger study that would include more participants, including those who are healthy but have a genetic risk for Alzheimer’s, and follow them for a longer time period with exercise in comparison to other types of treatments. He and his team hope to learn more about the impact of exercise on brain function and whether it could delay the onset or progression of Alzheimer’s disease.

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)

Scientists ID compounds that target amyloid fibrils in Alzheimer’s, other brain diseases

UCLA chemists and molecular biologists have for the first time used a “structure-based” approach to drug design to identify compounds with the potential to delay or treat Alzheimer’s disease, and possibly Parkinson’s, Lou Gehrig’s disease and other degenerative disorders.

All of these diseases are marked by harmful, elongated, rope-like structures known as amyloid fibrils, linked protein molecules that form in the brains of patients.

Structure-based drug design, in which the physical structure of a targeted protein is used to help identify compounds that will interact with it, has already been used to generate therapeutic agents for a number of infectious and metabolic diseases.

The UCLA researchers, led by David Eisenberg, director of the UCLA–Department of Energy Institute of Genomics and Proteomics and a Howard Hughes Medical Institute investigator, report the first application of this technique in the search for molecular compounds that bind to and inhibit the activity of the amyloid-beta protein responsible for forming dangerous plaques in the brain of patients with Alzheimer’s and other degenerative diseases.

In addition to Eisenberg, who is also a professor of chemistry, biochemistry and biological chemistry and a member of UCLA’s California NanoSystems Institute, the team included lead author Lin Jiang, a UCLA postdoctoral scholar in Eisenberg’s laboratory and Howard Hughes Medical Institute researcher, and other UCLA faculty.

The research was published July 16 in eLife, a new open-access science journal backed by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.

A number of non-structure-based screening attempts have been made to identify natural and synthetic compounds that might prevent the aggregation and toxicity of amyloid fibrils. Such studies have revealed that polyphenols, naturally occurring compounds found in green tea and in the spice turmeric, can inhibit the formation of amyloid fibrils. In addition, several dyes have been found to reduce amyloid’s toxic effects, although significant side effects prevent them from being used as drugs.

Armed with a precise knowledge of the atomic structure of the amyloid-beta protein, Jiang, Eisenberg and colleagues conducted a computational screening of 18,000 compounds in search of those most likely to bind tightly and effectively to the protein.

Those compounds that showed the strongest potential for binding were then tested for their efficacy in blocking the aggregation of amyloid-beta and for their ability to protect mammalian cells grown in culture from the protein’s toxic effects, which in the past has proved very difficult. Ultimately, the researchers identified eight compounds and three compound derivatives that had a significant effect.

While these compounds did not reduce the amount of protein aggregates, they were found to reduce the protein’s toxicity and to increase the stability of amyloid fibrils — a finding that lends further evidence to the theory that smaller assemblies of amyloid-beta known as oligomers, and not the fibrils themselves, are the toxic agents responsible for Alzheimer’s symptoms.

The researchers hypothesize that by binding snugly to the protein, the compounds they identified may be preventing these smaller oligomers from breaking free of the amyloid-beta fibrils, thus keeping toxicity in check.

An estimated 5 million patients in the U.S. suffer from Alzheimer’s disease, the most common form of dementia. Alzheimer’s health care costs in have been estimated at $178 billion per year, including the value of unpaid care for patients provided by nearly 10 million family members and friends.

In addition to uncovering compounds with therapeutic potential for Alzheimer’s disease, this research presents a new approach for identifying proteins that bind to amyloid fibrils — an approach that could have broad applications for treating many diseases.

Key Molecular Pathways Leading to Alzheimer’s Identified

Key molecular pathways that ultimately lead to late-onset Alzheimer’s disease, the most common form of the disorder, have been identified by researchers at Columbia University Medical Center (CUMC). The study, which used a combination of systems biology and cell biology tools, presents a new approach to Alzheimer’s disease research and highlights several new potential drug targets. The paper was published today in the journal Nature.

Much of what is known about Alzheimer’s comes from laboratory studies of rare, early-onset, familial (inherited) forms of the disease. “Such studies have provided important clues as to the underlying disease process, but it’s unclear how these rare familial forms of Alzheimer’s relate to the common form of the disease,” said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC. “Most important, dozens of drugs that ‘work’ in mouse models of familial disease have ultimately failed when tested in patients with late-onset Alzheimer’s. This has driven us, and other laboratories, to pursue mechanisms of the common form of the disease.”

Non-familial Alzheimer’s is complex; it is thought to be caused by a combination of genetic and environmental risk factors, each having a modest effect individually. Using so-called genome-wide association studies (GWAS), prior reports have identified a handful of common genetic variants that increase the likelihood of Alzheimer’s. A key goal has been to understand how such common genetic variants function to impact the likelihood of Alzheimer’s.

In the current study, the CUMC researchers identified key molecular pathways that link such genetic risk factors to Alzheimer’s disease. The work combined cell biology studies with systems biology tools, which are based on computational analysis of the complex network of changes in the expression of genes in the at-risk human brain.

More specifically, the researchers first focused on the single most significant genetic factor that puts people at high risk for Alzheimer’s, called APOE4 (found in about a third of all individuals). People with one copy of this genetic variant have a three-fold increased risk of developing late-onset Alzheimer’s, while those with two copies have a ten-fold increased risk. “In this study,” said Dr. Abeliovich, “we initially asked: If we look at autopsy brain tissue from individuals at high risk for Alzheimer’s, is there a consistent pattern?”

Surprisingly, even in the absence of Alzheimer’s disease, brain tissue from individuals at high risk (who carried APOE4 in their genes) harbored certain changes reminiscent of those seen in full-blown Alzheimer’s disease,” said Dr. Abeliovich. “We therefore focused on trying to understand these changes, which seem to put people at risk. The brain changes we considered were based on ‘transcriptomics’—a broad molecular survey of the expression levels of the thousands of genes expressed in brain.”

Using the network analysis tools mentioned above, the researchers then identified a dozen candidate “master regulator” factors that link APOE4 to the cascade of destructive events that culminates in Alzheimer’s dementia. Subsequent cell biology studies revealed that a number of these master regulators are involved in the processing and trafficking of amyloid precursor protein (APP) within brain neurons. APP gives rise to amyloid beta, the protein that accumulates in the brain cells of patients with Alzheimer’s. In sum, the work ultimately connected the dots between a common genetic factor that puts individuals at high risk for Alzheimer’s, APOE4, and the disease pathology.

Among the candidate “master regulators” identified, the team further analyzed two genes, SV2A and RFN219. “We were particularly interested in SV2A, as it is the target of a commonly used anti-epileptic drug, levetiracetam. This suggested a therapeutic strategy. But more research is needed before we can develop clinical trials of levetiracetam for patients with signs of late-onset Alzheimer’s disease.”

The researchers evaluated the role of SV2A, using human-induced neurons that carry the APOE4 genetic variant. (The neurons were generated by directed conversion of skin fibroblasts from individuals at high risk for Alzheimer’s, using a technology developed in the Abeliovich laboratory.) Treating neurons that harbor the APOE4 at-risk genetic variant with levetiracetam (which inhibits SV2A) led to reduced production of amyloid beta. The study also showed that RFN219 appears to play a role in APP-processing in cells with the APOE4 variant.

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.”

Fighting Alzheimer’s disease with protein origami

The human protein prefoldin can reduce the neuronal toxicity of clumps of amyloid-β proteins that collect in the brains of Alzheimer’s patients

Alzheimer’s disease is a progressive degenerative brain disease most commonly characterized by memory deficits. Loss of memory function, in particular, is known to be caused by neuronal damage arising from the misfolding of protein fragments in the brain. Now, a group of researchers led by Mizuo Maeda of the RIKEN Bioengineering Laboratory, and including researchers from the Laboratory for Proteolytic Neuroscience at the RIKEN Brain Science Institute, has found that the human protein prefoldin can change the way these misfolded protein aggregates form and potentially reduce their toxic impact on the brains of Alzheimer’s patients.

The formation of insoluble fibril aggregates of the protein amyloid-β has been identified as a key mechanism responsible for memory loss in Alzheimer’s patients. These fibrils are toxic to neurons, and finding a means of preventing their formation represents a key strategy in the development of a therapy for the disease. Recent studies suggest methods that alter the mechanism of amyloid-β aggregates could offer a promising approach.

Prefoldin is a molecular chaperone involved in preventing the clumping of misfolded proteins and helping misfolded proteins return to their normal shape. The researchers found that amyloid-β molecules incubated with even just a small amount of human prefoldin underwent a change in aggregation behavior—they instead formed into small, soluble oligomer clumps. The observations suggest that human prefoldin interacts with amyloid-β molecules to alter their binding properties.

As in the brain, amyloid-β fibrils also kill neurons in cell culture. Using neurons from the brains of mice, the researchers showed that the amyloid-β oligomers formed in the presence of human prefoldin induced less neuron death than amyloid-β fibrils. Prefoldin expression actually increases in the brains of mice with high levels of amyloid-β, suggesting that the upregulation of prefoldin expression might be a response mechanism used by the brain to protect itself from the toxic effects of amyloid-β fibrils.

Many researchers currently believe that amyloid-β oligomers are themselves a toxin that induces neuronal dysfunction. The present results, however, suggest that certain types of oligomers may in fact be less toxic than other conformations of amyloid-β aggregates. Increasing the expression of human prefoldin in the brain may therefore increase the proportion of less toxic amyloid-β aggregates, presenting a potential means of fighting the disease.

“Our findings may also apply to various other neurological diseases caused by protein misfolding, such as prion disease, Huntington’s disease and Parkinson’s disease,” explains Tamotsu Zako from the research team.