A new strategy required in the search for Alzheimer’s drugs?

In the search for medication against Alzheimer’s disease, scientists have focused – among other factors – on drugs that can break down Amyloid beta (A-beta). After all, it is the accumulation of A-beta that causes the known plaques in the brains of Alzheimer’s patients. Starting point for the formation of A-beta is APP. Alessia Soldano and Bassem Hassan (VIB/KU Leuven) were the first to unravel the function of APPL – the fruit-fly version of APP – in the brain of healthy fruit flies. (PLoS Biology)

Alessia Soldano (VIB/KU Leuven): “We have discovered that APPL ensures that brain cells form a good network. We now have to ask ourselves the question whether this function of APPL is also relevant to Alzheimer’s disease.”

Bassem Hassan (VIB/KU Leuven): “Since we show that APP and APPL show similar activities in cultured cells, we suspect that APP in the human brain functions in the same manner as APPL in the brain of fruit flies. Hopefully we can use this to ask and eventually answer the question whether A-beta or APP itself is the better target for new drugs.”

Plaques in the brain: cause or effect
The brain of a person with Alzheimer’s disease is very recognizable due to the so-called plaques. A plaque is an accumulation of proteins that are primarily made up of Amyloid beta (A-beta), a small structure that splits off from the Amyloid Precursor Protein (APP). We have been dreaming for a long time of a drug that can break down A-beta, but we should be asking ourselves whether this is really the best strategy. After all, it is not yet clear whether the plaques are a cause or effect of Alzheimer’s disease. In order to answer this question, it is important to determine the function of APP in healthy brains.

Optimum communication between brain cells
Alessia Soldano and Bassem Hassan study APPL, the fruit-fly version of APP. APPL is found throughout the fruit-fly brain, but primarily in the so-called alpha-beta neurons that are vital to learning processes and memory. The alpha-beta neurons must form functional axons for optimum functioning. Axons are tendrils projecting from the neuron, which are essential for communication between neurons. The VIB scientists had previously shown that APPL is important for memory in flies. Now, they have discovered that – in the developing brain of a fruit fly – APPL ensures that the axons are long enough and grow in the correct direction. APPL is therefore essential in the formation of a good network of neurons. The question is whether or not it is a good strategy to target a protein with such an important function in the brain in order to combat Alzheimer’s disease. (PLoS Biology)

Scientists Discover Cinnamon Compounds’ Potential Ability to Prevent Alzheimer’s

Cinnamon: Can the red-brown spice with the unmistakable fragrance and variety of uses offer an important benefit? The common baking spice might hold the key to delaying the onset of –– or warding off –– the effects of Alzheimer’s disease.

That is, according to Roshni George and Donald Graves, scientists at UC Santa Barbara. The results of their study, “Interaction of Cinnamaldehyde and Epicatechin with Tau: Implications of Beneficial Effects in Modulating Alzheimer’s Disease Pathogenesis,” appears in the online early edition of the Journal of Alzheimer’s Disease, and in the upcoming Volume 36, issue 1 print edition.

Alzheimer’s disease is the most common form of dementia, a neurodegenerative disease that progressively worsens over time as it kills brain cells. No cure has yet been found, nor has the major cause of Alzheimer’s been identified.

However, two compounds found in cinnamon –– cinnamaldehyde and epicatechin –– are showing some promise in the effort to fight the disease. According to George and Graves, the compounds have been shown to prevent the development of the filamentous “tangles” found in the brain cells that characterize Alzheimer’s.

Responsible for the assembly of microtubules in a cell, a protein called tau plays a large role in the structure of the neurons, as well as their function.

"The problem with tau in Alzheimer’s is that it starts aggregating," said George, a graduate student researcher. When the protein does not bind properly to the microtubules that form the cell’s structure, it has a tendency to clump together, she explained, forming insoluble fibers in the neuron. The older we get the more susceptible we are to these twists and tangles; Alzheimer’s patients develop them more often and in larger amounts.

The use of cinnamaldehyde, the compound responsible for the bright, sweet smell of cinnamon, has proven effective in preventing the tau knots. By protecting tau from oxidative stress, the compound, an oil, could inhibit the protein’s aggregation. To do this, cinnamaldehyde binds to two residues of an amino acid called cysteine on the tau protein. The cysteine residues are vulnerable to modifications, a factor that contributes to the development of Alzheimer’s.

"Take, for example, sunburn, a form of oxidative damage," said Graves, adjunct professor in UCSB’s Department of Molecular, Cellular, and Developmental Biology. "If you wore a hat, you could protect your face and head from the oxidation. In a sense this cinnamaldehyde is like a cap." While it can protect the tau protein by binding to its vulnerable cysteine residues, it can also come off, Graves added, which can ensure the proper functioning of the protein.

Oxidative stress is a major factor to consider in the health of cells in general. Through normal cellular processes, free radical-generating substances like peroxides are formed, but antioxidants in the cell work to neutralize them and prevent oxidation. Under some conditions however, the scales are tipped, with increased production of peroxides and free radicals, and decreased amounts of antioxidants, leading to oxidative stress.

Epicatechin, which is also present in other foods, such as blueberries, chocolate, and red wine, has proven to be a powerful antioxidant. Not only does it quench the burn of oxidation, it is actually activated by oxidation so the compound can interact with the cysteines on the tau protein in a way similar to the protective action of cinnamaldehyde.

"Cell membranes that are oxidized also produce reactive derivatives, such as Acrolein, that can damage the cysteines," said George. "Epicatechin also sequesters those byproducts."

Studies indicate that there is a high correlation between Type 2 diabetes and the incidence of Alzheimer’s disease. The elevated glucose levels typical of diabetes lead to the overproduction of reactive oxygen species, resulting in oxidative stress, which is a common factor in both diabetes and Alzheimer’s disease. Other research has shown cinnamon’s beneficial effects in managing blood glucose and other problems associated with diabetes.

"Since tau is vulnerable to oxidative stress, this study then asks whether Alzheimer’s disease could benefit from cinnamon, especially looking at the potential of small compounds," said George.

Although this research shows promise, Graves said, they are “still a long way from knowing whether this will work in human beings.” The researchers caution against ingesting more than the typical amounts of cinnamon already used in cooking.

If cinnamon and its compounds do live up to their promise, it could be a significant step in the ongoing battle against Alzheimer’s. A major risk factor for the disease –– age –––– is uncontrollable. In the United States, Alzheimer’s presents a particular problem as the population lives longer and the Baby Boom generation turns gray, leading to a steep rise in the prevalance of the disease. It is a phenomenon that threatens to overwhelm the U.S. health care system. According to the Alzheimer’s Association, in 2013, Alzheimer’s disease will cost the nation $203 billion.

"Wouldn’t it be interesting if a small molecule from a spice could help?" commented Graves, "perhaps prevent it, or slow down the progression."

(Image: iStockphoto)

B vitamins could delay dementia

Despite spending billions of dollars on research and development, drug companies have been unable to come up with effective treatments for dementia and Alzheimer’s Disease (AD). Now, A. David Smith at the University of Oxford and his colleagues have discovered that, in some patients experiencing mild cognitive impairment (MCI), a cocktail of high-dose B vitamins could prevent gray matter loss associated with progression to AD. The study appears in the Proceedings of the National Academy of Sciences.

The World Health Organization predicts that between 2010 and 2050 the number of dementia cases will increase from 26 million to 115 million worldwide. Although there is an urgent demand for treatment, pharmaceutical companies have been unable to develop drugs that will delay or cure dementia. So far, approved drugs merely ease symptoms.

Smith and his team wanted to see if B vitamins reduced the risk of AD by lowering total homocysteine (tHcy) levels. There is a positive correlation between high tHcy levels and risk of cognitive impairment and AD.

The researchers studied 156 subjects over 70 in Oxford, England who suffered from MCI. The subjects received either a placebo or a high-dose B vitamin cocktail consisting of 20 milligrams of vitamin B6, 0.5 milligrams of vitamin B12 and 0.8 milligrams of folic acid.

Over a two-year period, subjects in both the experimental and control groups lost gray matter in the medial temporal, lateral temporoparietal and occipital regions and in the anterior and posterior cingulate cortex.

However, those receiving B vitamin treatment experienced significantly less atrophy in regions of the brain most affected in people with AD and people with MCI who go on to develop AD. These include the bilateral hippocampus, the parahippocampal gyrus, the retrosplenial precuneus, the lingual gyrus, the fusiform gyrus and the cerebellum. The placebo group experienced a 3.7 percent loss of gray matter in these regions, compared with a 0.5 percent loss among the experimental group.

When they looked at baseline tHcy levels, Smith and his colleagues found that B-vitamin treatment did not significantly reduce gray matter atrophy among subjects with tHcy levels below the median. The B-vitamin cocktail did have a significant effect on high-tHcy participants: those receiving the cocktail experienced only a 0.6 percent loss of gray matter, while high-tHcy participants in the placebo group experienced a 5.2 percent loss.

The team found a correlation between gray matter loss and worsening of scores on tests that measure cognitive function.

A causal Bayesian network analysis showed that B vitamins lower tHcy levels. This decreases gray matter atrophy, which delays cognitive decline.

Drugs found to both prevent and treat Alzheimer’s disease in mice

Researchers at USC have found that a class of pharmaceuticals can both prevent and treat Alzheimer’s Disease in mice.

The drugs, known as “TSPO ligands,” are currently used for certain types of neuroimaging.

"We looked at the effects of TSPO ligand in young adult mice when pathology was at an early stage, and in aged mice when pathology was quite severe," said lead researcher Christian Pike of the USC Davis School of Gerontology. "TSPO ligand reduced measures of pathology and improved behavior at both ages."

The team’s findings were published online by the Journal of Neuroscience on May 15. Pike’s coauthors include USC postdoctoral scientists Anna M. Barron, Anusha Jayaraman and Joo-Won Lee; as well as Donatella Caruso and Roberto C. Melcangi of the University of Milan and Luis M. Garcia-Segura of the Instituto Cajal in Spain.

The most surprising finding for Pike and his team was the effect of TSPO ligand in the aged mice. Four treatments—once per week over four weeks—in older mice resulted in a significant decrease of Alzheimer’s-related symptoms and improvements in memory – meaning that TSPO ligands may actually reverse some elements of Alzheimer’s disease.

"Our data suggests the possibility of drugs that can prevent and treat Alzheimer’s," Pike said. "It’s just mouse data, but extremely encouraging mouse data. There is a strong possibility that TSPO ligands similar to the ones used in our study could be evaluated for therapeutic efficacy in Alzheimer’s patients within the next few years."

Next, the team will next focus on understanding how TSPO ligands reduce Alzheimer’s disease pathology. Building on the established knowledge that TSPO ligands can reduce inflammation—shielding nerve cells from injury and increasing the production of neuroactive hormones in the brain—the team will study which of these actions is the most significant in fighting Alzheimer’s disease so they can develop newer TSPO ligands accordingly.

Scientists identify molecular trigger for Alzheimer’s disease

Researchers have pinpointed a catalytic trigger for the onset of Alzheimer’s disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons in the brain.

For the first time, scientists at Cambridge’s Department of Chemistry, led by Dr Tuomas Knowles, Professor Michele Vendruscolo and Professor Chris Dobson working with Professor Sara Linse and colleagues at Lund University in Sweden have been able to map in detail the pathway that generates “aberrant” forms of proteins which are at the root of neurodegenerative conditions such as Alzheimer’s.

They believe the breakthrough is a vital step closer to increased capabilities for earlier diagnosis of neurological disorders such as Alzheimer’s and Parkinson’s, and opens up possibilities for a new generation of targeted drugs, as scientists say they have uncovered the earliest stages of the development of Alzheimer’s that drugs could possibly target.

The study, published today in the Proceedings of the US National Academy of Sciences, is a milestone in the long-term research established in Cambridge by Professor Christopher Dobson and his colleagues, following the realisation by Dobson of the underlying nature of protein ‘misfolding’ and its connection with disease over 15 years ago.

The research is likely to have a central role to play in diagnostic and drug development for dementia-related diseases, which are increasingly prevalent and damaging as populations live longer.

In 2010, the Alzheimer’s Research UK showed that dementia costs the UK economy over £23 billion, more than cancer and heart disease combined. Just last week, PM David Cameron urged scientists and clinicians to work together to “improve treatments and find scientific breakthroughs” to address “one of the biggest social and healthcare challenges we face.”

The neurodegenerative process giving rise to diseases such as Alzheimer’s is triggered when the normal structures of protein molecules within cells become corrupted.

Protein molecules are made in cellular ‘assembly lines’ that join together chemical building blocks called amino acids in an order encoded in our DNA. New proteins emerge as long, thin chains that normally need to be folded into compact and intricate structures to carry out their biological function.

Under some conditions, however, proteins can ‘misfold’ and snag surrounding normal proteins, which then tangle and stick together in clumps which build to masses, frequently millions, of malfunctioning molecules that shape themselves into unwieldy protein tendrils.

The abnormal tendril structures, called ‘amyloid fibrils’, grow outwards around the location where the focal point, or ‘nucleation’ of these abnormal “species” occurs.

Amyloid fibrils can form the foundations of huge protein deposits – or plaques – long-seen in the brains of Alzheimer’s sufferers, and once believed to be the cause of the disease, before the discovery of ‘toxic oligomers’ by Dobson and others a decade or so ago.

A plaque’s size and density renders it insoluble, and consequently unable to move. Whereas the oligomers, which give rise to Alzheimer’s disease, are small enough to spread easily around the brain - killing neurons and interacting harmfully with other molecules - but how they were formed was until now a mystery.

The new work, in large part carried out by researcher Samuel Cohen, shows that once a small but critical level of malfunctioning protein ‘clumps’ have formed, a runaway chain reaction is triggered that multiplies exponentially the number of these protein composites, activating new focal points through ‘nucleation’.

It is this secondary nucleation process that forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules. Small and highly diffusible, these are the ‘toxic oligomers’ that careen dangerously around the brain cells, killing neurons and ultimately causing loss of memory and other symptoms of dementia.

“There are no disease modifying therapies for Alzheimer’s and dementia at the moment, only limited treatment for symptoms. We have to solve what happens at the molecular level before we can progress and have real impact,” said Dr Tuomas Knowles from Cambridge’s Department of Chemistry, lead author of the study and long-time collaborator of Professor Dobson and Professor Michele Vendruscolo.

“We’ve now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed. This is the key pathway to detect, target and intervene – the molecular catalyst that underlies the pathology.”

The researchers brought together kinetic experiments with a theoretical framework based on master equations, tools commonly used in other areas of chemistry and physics but had not been exploited to their full potential in the study of protein malfunction before.

The latest research follows hard on the heels of another ground breaking study, published in April of this year again in PNAS, in which the Cambridge group, in Collaboration with Colleagues in London and at MIT, worked out the first atomic structure of one of the damaging amyloid fibril protein tendrils. They say the years spent developing research techniques are really paying off now, and they are starting to solve “some of the key mysteries” of these neurodegenerative diseases.

“We are essentially using a physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to ‘recreate the crime scene’ at the molecular root of Alzheimer’s disease,” explained Knowles.

“Increasingly, using quantitative experimental tools and rigorous theoretical analysis to understand complex biological processes are leading to exciting and game-changing results. With a disease like Alzheimer’s, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we’ve found how the oligomers are created, we know what process we need to turn off.”

Study finds that sleep apnea and Alzheimer’s are linked

A new study looking at sleep-disordered breathing (SDB) and markers for Alzheimer’s disease (AD) risk in cerebrospinal fluid (CSF) and neuroimaging adds to the growing body of research linking the two.

But this latest study also poses an interesting question: Could AD in its “preclinical stages” also lead to SDB and explain the increased prevalence of SDB in the elderly?

The study will be presented at the ATS 2013 International Conference.

"It’s really a chicken and egg story," said Ricardo S. Osorio, MD, a research assistant professor at NYU School of Medicine who led the study. "Our study did not determine the direction of the causality, and, in fact, didn’t uncover a significant association between the two, until we broke out the data on lean and obese patients."

When the researchers did consider body mass, they found that lean patients (defined as having a body mass index <25) with SDB did possess several specific and non-specific biomarkers of AD risk (increased P-Tau and T-Tau in CSF, hippocampal atrophy using structural MRI, and glucose hypometabolism using FDG-PET in several AD-vulnerable regions). Among obese patients (BMI >25), glucose hypometabolism was also found in the medial temporal lobe, but was not significant in other AD-vulnerable regions.

"We know that about 10 to 20 percent of middle-aged adults in the United States have SDB [defined as an apnea-hypopnea index greater than 5] and that the number jumps dramatically in those over the age of 65," said Dr. Osorio, noting that studies put the percentage of people over the age of 65 with SDB between 30 and 60 percent. "We don’t know why it becomes so prevalent, but one factor may be that some of these patients are in the earliest preclinical stages of AD."

According to Dr. Osorio, the biochemical harbingers of AD are present 15 to 20 years before any of its currently recognized symptoms become apparent.

The NYU study enrolled 68 cognitively normal elderly patients (mean age 71.4±5.6, range 64-87) who underwent two nights of home monitoring for SDB and were tested for at least one diagnostic indicator of AD. The researchers looked at P-Tau, T-Tau and Aβ42 in CSF, FDG-PET (to measure glucose metabolism), Pittsburgh compound B (PiB) PET to measure amyloid load, and/or structural MRI to measure hippocampal volume. Reduced glucose metabolism in AD-vulnerable regions, decreased hippocampal volume, changes in P-Tau, T-Tau and Aβ42, and increased binding of PiB-PET are recognized as markers of risk for AD and have been reported to be abnormal in healthy subjects before the disease onset.

Biomarkers for AD risk were found only among lean study participants with SDB. These patients showed a linear association between the severity of SDB and CSF levels of the biomarker P-Tau (F = 5.83, t=2.41, β=0.47; p< 0.05) and between SDB and glucose hypometabolism using FDG-PET, in the medial temporal lobe (F=6.34, t=-2.52, β=-0.57,p<0.05), the posterior cingulate cortex/precuneus (F=11.62, t=-3.41, β=-0.69, p<0.01) and a composite score of all AD-vulnerable regions (F=4.48, t=-2.11, β=-0.51, p<0.05). Lean SDB patients also showed smaller hippocampi when compared to lean controls (F=4.2, p<0.05), but no differences were found in measures of amyloid burden such as decreased Aβ42 in CSF or PiB positive scans.

Dr. Osorio and his colleagues are planning to test their hypothesis that very early stage preclinical AD brain injury that associates with these biomarkers can lead to SDB. They have proposed a two-year longitudinal study that would enroll 200 cognitively normal subjects, include AD biomarkers and treat those patients with moderate to severe SDB with continuous positive airway pressure, or CPAP, over time.

The purpose of the new study would be to determine the “direction” of causality between SDB and preclinical AD in elderly patients. After an initial assessment, the patients would be given CPAP to treat their sleep apnea. After six months, they would be evaluated again for biomarker evidence of AD.

"If the biomarkers change, it may indicate that SDB is causing AD," explained Dr. Osorio. "If they don’t change, the probable conclusion is that these patients are going to develop AD with or without CPAP, and that AD may either be causing the apneas or may simply coexist with SDB as part of aging."

Either way, Dr. Osorio believes the relationship between SDB and AD deserves further study.

"Sleep apnea skyrockets in the elderly, and this fact hasn’t been given the attention it deserves by the sleep world or the Alzheimer’s world," Dr. Osorio said. "Sleep particularly suffers from an outmoded perception that it is an inactive physiological process, when, in reality, it is a very active part of the day for the brain."

Brain rewires itself after damage or injury

When the brain’s primary “learning center” is damaged, complex new neural circuits arise to compensate for the lost function, say life scientists from UCLA and Australia who have pinpointed the regions of the brain involved in creating those alternate pathways — often far from the damaged site.

The research, conducted by UCLA’s Michael Fanselow and Moriel Zelikowsky in collaboration with Bryce Vissel, a group leader of the neuroscience research program at Sydney’s Garvan Institute of Medical Research, appears this week in the early online edition of the journal Proceedings of the National Academy of Sciences.

The researchers found that parts of the prefrontal cortex take over when the hippocampus, the brain’s key center of learning and memory formation, is disabled. Their breakthrough discovery, the first demonstration of such neural-circuit plasticity, could potentially help scientists develop new treatments for Alzheimer’s disease, stroke and other conditions involving damage to the brain.

For the study, Fanselow and Zelikowsky conducted laboratory experiments with rats showing that the rodents were able to learn new tasks even after damage to the hippocampus. While the rats needed more training than they would have normally, they nonetheless learned from their experiences — a surprising finding.

"I expect that the brain probably has to be trained through experience," said Fanselow, a professor of psychology and member of the UCLA Brain Research Institute, who was the study’s senior author. "In this case, we gave animals a problem to solve."

After discovering the rats could, in fact, learn to solve problems, Zelikowsky, a graduate student in Fanselow’s laboratory, traveled to Australia, where she worked with Vissel to analyze the anatomy of the changes that had taken place in the rats’ brains. Their analysis identified significant functional changes in two specific regions of the prefrontal cortex.

"Interestingly, previous studies had shown that these prefrontal cortex regions also light up in the brains of Alzheimer’s patients, suggesting that similar compensatory circuits develop in people," Vissel said. "While it’s probable that the brains of Alzheimer’s sufferers are already compensating for damage, this discovery has significant potential for extending that compensation and improving the lives of many."

The hippocampus, a seahorse-shaped structure where memories are formed in the brain, plays critical roles in processing, storing and recalling information. The hippocampus is highly susceptible to damage through stroke or lack of oxygen and is critically inolved in Alzheimer’s disease, Fanselow said.

"Until now, we’ve been trying to figure out how to stimulate repair within the hippocampus," he said. "Now we can see other structures stepping in and whole new brain circuits coming into being."

Zelikowsky said she found it interesting that sub-regions in the prefrontal cortex compensated in different ways, with one sub-region — the infralimbic cortex — silencing its activity and another sub-region — the prelimbic cortex — increasing its activity.

"If we’re going to harness this kind of plasticity to help stroke victims or people with Alzheimer’s," she said, "we first have to understand exactly how to differentially enhance and silence function, either behaviorally or pharmacologically. It’s clearly important not to enhance all areas. The brain works by silencing and activating different populations of neurons. To form memories, you have to filter out what’s important and what’s not."

Complex behavior always involves multiple parts of the brain communicating with one another, with one region’s message affecting how another region will respond, Fanselow noted. These molecular changes produce our memories, feelings and actions.

"The brain is heavily interconnected — you can get from any neuron in the brain to any other neuron via about six synaptic connections," he said. "So there are many alternate pathways the brain can use, but it normally doesn’t use them unless it’s forced to. Once we understand how the brain makes these decisions, then we’re in a position to encourage pathways to take over when they need to, especially in the case of brain damage.

"Behavior creates molecular changes in the brain; if we know the molecular changes we want to bring about, then we can try to facilitate those changes to occur through behavior and drug therapy," he added. I think that’s the best alternative we have. Future treatments are not going to be all behavioral or all pharmacological, but a combination of both."