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.

Researchers Investigate Mechanism of Alzheimer’s Therapy

Researchers at the University of Kentucky Sanders-Brown Center on Aging, led by faculty member Donna Wilcock, have recently published a new paper in the Journal of Neuroscience detailing an advance in treatment of Alzheimer’s disease.

Gammagard™ IVIg is a therapy that has been investigated for treatment of Alzheimer’s. Despite small clinical studies that have reported efficacy of the approach, the mechanism of action is poorly understood.

The UK researchers set out to investigate the mechanism by which the treatment may act in the brain to lower amyloid deposition (amyloid deposits being a key pathology in Alzheimer’s).

To conduct their investigation, researchers introduced IVIg directly into the brains of mice which carry a human gene causing them to develop amyloid plaques. They found that IVIg lowers amyloid deposits in the brains of the mice over the course of seven days. Their data suggest that the modulation of inflammation in the brain by IVIg is a key event that leads to the reduction in amyloid deposition.

The scientists hypothesize that the IVIg acts as an immune modulator, and this immune modulation is responsible for the reductions in amyloid pathology.

The data suggests that modulating the immune response in the brain may help ameliorate the Alzheimer’s pathology. Researchers are currently investigating other ways to produce the same modulation of the immune response because the access of IVIg to the brain when administered peripherally is very limited.

To Preserve Memory Into Old Age, Keep Your Brain Active!

A new study from Rush University Medical Center in Chicago claims reading and writing may preserve memory into old age. By keeping your brain active, says study author Robert S. Wilson, PhD, you’re able to slow the rate at which your memory decreases in later years.

This is not the first time researchers have arrived at such a conclusion, of course. Previous studies have also found keeping the brain active by reading, writing, completing crossword puzzles and more can essentially exercise the brain and keep it limber far into old age. One study also concluded that keeping television consumption to a minimal amount may also boost brain power over the years. Wilson’s study was recently published in the journal Neurology.

“Our study suggests that exercising your brain by taking part in activities such as these across a person’s lifetime, from childhood through old age, is important for brain health in old age,” said Wilson in a statement.

For his study, Wilson gathered nearly 300 people around the age of 80. He then gave them tests which were designed to measure both their memory and cognition each year until they passed away at an average age of 89. The same participants also answered questions about their past, such as whether they read books, did any writing, or engaged in any other mentally stimulating activities. The volunteers answered these questions for every part of their life, from childhood to adolescence, middle age and beyond.

When the participants passed away, their brains were then examined at an autopsy as Wilson’s team looked for physical evidence of dementia, such as lesions in the brain, tangles or plaques. After examining the brains of these volunteers and compiling the data from the questionnaires, Wilson’s team found those who had kept their minds active throughout their lives had a slower rate of memory decline than those who did not often participate in mentally challenging activities. Based on the amount of plaques and tangles in the brains, keeping your brain active is responsible for a 15 percent differential in memory decline.

The study also found the rate of memory decline was reduced by 32 percent in people who kept their brains active late in life. Those who were not mentally active had it much worse; their memories declined 48 percent faster than their actively reading and writing peers.

“Based on this, we shouldn’t underestimate the effects of everyday activities, such as reading and writing, on our children, ourselves and our parents or grandparents,” said Wilson.

And this news is hardly surprising. Doctors, teachers and parents have been admonishing children to turn off the television and pick up a book for years. There is no shortage of studies to back up their claims. A 2009 study, for example, found people who keep their brains active saw a 30 to 50 percent decrease in risk of developing memory loss. This study, conducted by doctors at the Mayo Clinic in Rochester, Minnesota observed people between the ages of 70 and 89 with and without diagnosed memory loss.

Those who were likely to read magazines or engage in other social activities were 40 percent less likely to develop memory loss than homebodies who did not read. Furthermore, those who spent less than seven hours a day watching television were 50 percent less likely to develop memory loss than those who planted themselves in front of the tube for long stretches of time.

Alzheimer’s Disease Mouse Models Point To A Potential Therapeutic Approach

Building on research published eight years ago in the journal Chemistry and Biology, Kenneth S. Kosik, Harriman Professor in Neuroscience and co-director of the Neuroscience Research Institute (NRI) at UC Santa Barbara, and his team have now applied their findings to two distinct, well-known mouse models, demonstrating a new potential target in the fight against Alzheimer’s and other neurodegenerative diseases.

The results were published online June 4 as the Paper of the Week in the Journal of Biological Chemistry. As a Paper of the Week, Kosik’s work is among the top 2 percent of manuscripts the journal reviews in a year. Based on significance and overall importance, between 50 and 100 papers are selected for this honor from the more than 6,600 published each year.

Kosik and his research team focused on tau, a protein normally present in the brain, which can develop into neurofibrillary tangles (NFTs) that, along with plaques containing amyloid-ß protein, characterize Alzheimer’s disease. When tau becomes pathological, many phosphate groups attach to it, causing it to become dysfunctional and intensely phosphorylated, or hyperphosphorylated. Aggregations of hyperphosphorylated tau are also referred to as paired helical filaments.

"What struck me most while working on this project was how so many people I’d never met came to me to share their stories and personal anxieties about Alzheimer’s disease," said Xuemei Zhang, lead co-author and an assistant specialist in the Kosik Lab. "There is no doubt that finding therapeutic treatment is the only way to help this fast-growing population." Israel Hernandez, a postdoctoral scholar of the NRI and UCSB’s Department of Molecular, Cellular and Developmental Biology, is the paper’s other lead co-author.

Treatments for hyperphosphorylated tau, one of the main causes of Alzheimer’s disease, do not exist. Current treatment is restricted to drugs that increase the concentration of neurotransmitters to promote signaling between neurons.

However, this latest research explores the possibility that a small class of molecules called diaminothiazoles can act as inhibitors of kinase enzymes that phosphorylate tau. Kosik’s team studied the toxicity and immunoreactivity of several diaminothiazoles that targeted two key kinases, CDK5/p25 and GSK3ß, in two Alzheimer’s disease mouse models. The investigators found that the compounds can efficiently inhibit the enzymes with hardly any toxic effects in the therapeutic dose range.

Treatment with the lead compound in this study, LDN-193594, dramatically affected the prominent neuronal cell loss that accompanies increased CDK5 activity. Diaminothiazole kinase inhibitors not only reduced tau phosphorylation but also exerted a neuroprotective effect in vivo. In addition to reducing the amount of the paired helical filaments in the mice’s brains, they also restored their learning and memory abilities during a fear-conditioning assay.

According to the authors, the fact that treatment with diaminothiazole kinase inhibitors reduced the phosphorylation of tau provides strong evidence that small molecular kinase inhibitor treatment could slow the progression of tau pathology. “Given the contribution of both CDK5 and GSK3ß to tau phosphorylation,” said Kosik, “effective treatment of tauopathies may require dual kinase targeting.”

Madison Cornwell, a Beckman Scholar with UCSB’s Center for Science and Engineering Partnerships who worked in Kosik’s lab, added: “As a beginning step, we demonstrated that two of these compounds were successful in clearing the brain of tau tangles in a mouse model, but someday inhibitors of these kinases may serve to ameliorate the symptoms of Alzheimer’s disease in patients.”

Promising Alzheimer’s ‘drug’ halts memory loss

A new class of experimental drug-like small molecules is showing great promise in targeting a brain enzyme to prevent early memory loss in Alzheimer’s disease, according to Northwestern Medicine® research.

Developed in the laboratory of D. Martin Watterson, the molecules halted memory loss and fixed damaged communication among brain cells in a mouse model of Alzheimer’s.

"This is the starting point for the development of a new class of drugs," said Watterson, lead author of a paper on the study and the John G. Searle Professor of Molecular Biology and Biochemistry at Northwestern University Feinberg School of Medicine. "It’s possible someday this class of drugs could be given early on to people to arrest certain aspects of Alzheimer’s."

Changes in the brain start to occur ten to 15 years before serious memory problems become apparent in Alzheimer’s.

"This class of drugs could be beneficial when the nerve cells are just beginning to become impaired," said Linda Van Eldik, a senior author of the paper and director of the University of Kentucky Sanders-Brown Center on Aging.

The study is a collaboration between Northwestern’s Feinberg School, Columbia University Medical Center and the University of Kentucky. It will be published June 26 in the journal PLOS ONE.

The novel drug-like molecule, called MW108, reduces the activity of an enzyme that is over-activated during Alzheimer’s and is considered a contributor to brain inflammation and impaired neuron function. Strong communication between neurons in the brain is an essential process for memory formation.

"I’m not aware of any other drug that has this effect on the central nervous system," Watterson said.

"These exciting results provide new hope for developing drugs against an important molecular target in the brain," said Roderick Corriveau, program director at the National Institute of Neurological Disorders and Stroke, which helped support the research. "They also provide a promising strategy for identifying small molecule drugs designed to treat Alzheimer’s disease and other neurological disorders."

Watterson and his collaborators have a new National Institutes of Health (NIH) award to further refine the compound so it is metabolically stable and safe for use in humans and develop it to the point of starting a phase 1 clinical trial.

(Image: Jay Vollmar)

Protein Linked to Cognitive Decline in Alzheimer’s Identified

Researchers at Columbia University Medical Center (CUMC) have demonstrated that a protein called caspase-2 is a key regulator of a signaling pathway that leads to cognitive decline in Alzheimer’s disease. The findings, made in a mouse model of Alzheimer’s, suggest that inhibiting this protein could prevent the neuronal damage and subsequent cognitive decline associated with the disease. The study was published this month in the online journal Nature Communications.

One of the earliest events in Alzheimer’s is disruption of the brain’s synapses (the small gaps across which nerve impulses are passed), which can lead to neuronal death. Although what drives this process has not been clear, studies have indicated that caspace-2 might be involved, according to senior author Michael Shelanski, MD, PhD, the Delafield Professor of Pathology & Cell Biology, chair of the Department of Pathology and Cell Biology, and co-director of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC.

Several years ago, in tissue culture studies of mouse neurons, Dr. Shelanski found that caspace-2 plays a critical role in the death of neurons in the presence of amyloid beta, the protein that accumulates in the neurons of people with Alzheimer’s. Other researchers have shown that caspase-2 also contributes to the maintenance of normal synaptic functions.

Dr. Shelanski and his team hypothesized that aberrant activation of caspase-2 may cause synaptic changes in Alzheimer’s disease. To test this hypothesis, the researchers crossed J20 transgenic mice (a common mouse model of Alzheimer’s) with caspase-2 null mice (mice that lack caspase-2). They compared the animals’ ability to negotiate a radial-arm water maze, a standard test of cognitive ability, with that of regular J20 mice and of normal mice at 4, 9, and 14 months of age.

The results for the three groups of mice were similar at the first two intervals. At 14 months, however, the J20/caspase-2 null mice did significantly better in the water maze test than the J20 mice and similarly to the normal mice. “We showed that removing caspase-2 from J20 mice prevented memory impairment — without significant changes in the level of soluble amyloid beta,” said co-lead author Roger Lefort, PhD, associate research scientist at CUMC.

Analysis of the neurons showed that the J20/caspase-2 null mice had a higher density of dendritic spines than the J20 mice. The more spines a neuron has, the more impulses it can transmit.

“The J20/caspase-2 null mice showed the same dendritic spine density and morphology as the normal mice—as opposed to the deficits in the J20 mice,” said co-lead author Julio Pozueta, PhD. “This strongly suggests that caspase-2 is a critical regulator in the memory decline associated with beta-amyloid in Alzheimer’s disease.”

The researchers further validated the results in studies of rat neurons in tissue culture.

Finally, the researchers found that caspase-2 interacts with RhoA, a critical regulator of the morphology (form and structure) of dendritic spines. “It appears that in normal neurons, caspase-2 and RhoA form an inactive complex outside the dendritic spines,” said Dr. Lefort. “When the complex is exposed to amyloid beta, it breaks apart, activating the two components.” Once activated, caspase-2 and RhoA enter the dendritic spines and contribute to their demise, possibly by interacting with a third molecule, the enzyme ROCK-II.

“This raises the possibility that if you can inhibit one or all of these molecules, especially early in the course of Alzheimer’s, you might be able to protect neurons and slow down the cognitive effects of the disease,” said Dr. Lefort.

Repairing Bad Memories

It was a Saturday night at the New York Psychoanalytic Institute, and the second-floor auditorium held an odd mix of gray-haired, cerebral Upper East Side types and young, scruffy downtown grad students in black denim. Up on the stage, neuroscientist Daniela Schiller, a riveting figure with her long, straight hair and impossibly erect posture, paused briefly from what she was doing to deliver a mini-lecture about memory.

She explained how recent research, including her own, has shown that memories are not unchanging physical traces in the brain. Instead, they are malleable constructs that may be rebuilt every time they are recalled. The research suggests, she said, that doctors (and psychotherapists) might be able to use this knowledge to help patients block the fearful emotions they experience when recalling a traumatic event, converting chronic sources of debilitating anxiety into benign trips down memory lane.

And then Schiller went back to what she had been doing, which was providing a slamming, rhythmic beat on drums and backup vocals for the Amygdaloids, a rock band composed of New York City neuroscientists. During their performance at the institute’s second annual “Heavy Mental Variety Show,” the band blasted out a selection of its greatest hits, including songs about cognition (“Theory of My Mind”), memory (“A Trace”), and psychopathology (“Brainstorm”).

“Just give me a pill,” Schiller crooned at one point, during the chorus of a song called “Memory Pill.” “Wash away my memories …”

The irony is that if research by Schiller and others holds up, you may not even need a pill to strip a memory of its power to frighten or oppress you.

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