Alzheimer's Advances and Swift Songbirds

16 February 2009
Presented by Ben Valsler.

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For this week's NewsFlash, we hear about a new drug that helps heart failure patients to be more active, explore the latest advances against Alzheimer's disease and discover how songbirds are surprisingly swift.  Plus, we find out about the genetic root of all teeth, and what it can tell us about the evolution of feathers and fur...

In this episode

Haemoglobin

Molecule muscles more oxygen off haemoglobin to boost performance and beat heart failure

Scientists have developed a new molecule that can provoke haemoglobin, the red oxygen-bearing pigment in blood, to release its oxygen cargo more readily, boosting muscle power.

HaemoglobinWriting in this week's PNAS, Boston University Medical Centre researcher Andreia Biolo and her colleagues describe a new molecule ITPP - myo-inositol trispyrophosphate - which can mimic the way the body adapts to high altitude by penetrating red blood cells and locking onto the haemoglobin molecules inside.  This causes the haemoglobin molecules to alter their shape slightly, loosening their grip on the oxygen molecules they pick up from the lungs.  As a result the cells give up the oxygen far more readily to the tissues.  Tests in healthy mice showed that ITPP-treated animals had 50% greater exercise endurance compared with their untreated littermates.

But even more encouragingly, when the agent was administered to animals with an inherited form of heart failure (a dilated cardiomyopathy), their capacity for exercise increased by 70% because the demands on the heart were lower because the animals' muscles were able to obtain the oxygen they needed at lower levels of blood flow.  This, say the researchers, may be a highly effective way to improve the lives of patients disabled by heart failure, particularly since ITPP seems to be orally-active in the experimental mice.  But they will, first, need to prove that the agent is safe first before human trials can begin.

Histopathogic image of senile plaques seen in the cerebral cortex in a patient with Alzheimer disease of pre-senile onset. Silver impregnation.

03:51 - New way to block Alzheimer's

Scientists have uncovered two new approaches to blocking the progression of Alzheimer's disease.

New way to block Alzheimer's

Scientists have uncovered two new approaches to blocking the progression of Alzheimer's disease.  The two separate studies, one from a Belgian group of researchers from the Catholic University of Leuven and published in the journal Science and the other from an NIH team in Bethesda, US and published in PNAS, focus on the mechanism by which a protein called beta amyloid, which builds up in the brains of Alzheimer's patients, is formed and how it harms cells.

Alzheimers Senile Plaques
Histopathogic image of senile plaques seen in the cerebral cortex in a patient with Alzheimer disease of pre-senile onset. Silver impregnation. © KGH

In the Science paper Amantha Thathiah and colleagues used a genetic technique to look for chemical messengers that, when added to cells, increased beta amyloid production.  Using this approach they were able to home in on a signalling molecule called G protein-coupled receptor 3 (GPR-3), which turns on an enzyme called gamma-secretase, which in turn produces beta amyloid.  As the team expected, turning off the molecule reduced beta-amyloid production whilst boosting its levels increased beta-amyloid.  Encouragingly, GPR-3 is only expressed in the brain, which means it might be possible to engineer a drug designed to target selectively this receptor, thus minimising the side effects, which have plagued earlier anti-Alzheimer's drug strategies.

Meanwhile, the PNAS paper by Juan Carlos Diaz and his colleagues tests the theory that the beta-amyloid that builds up in the brain damages nerve cells by forming new pores in the nerve cell membranes.  These pores allow calcium to flow into the cell, causing it to become over-excited and die.  To combat the problem the team have engineered two new drug molecules, which have been designed specifically to block up these hypothetical pores.

Working with cultured cells the team added beta amyloid alone or beta amyloid plus one of the two blocking drugs and used sensitive measuring techniques to monitor the flow of calcium into the cells.  Cells incubated with just beta amyloid showed high levels of cell death preceeded by calcium flowing in.  But cells treated with the two new compounds showed equivalent survival rates to untreated control cells.

"If the neurotoxic mechanism for amyloid beta is the formation of toxic calcium channels, then compounds that block the channels can logically be considered candidate Alzheimer's drugs," says the researchers.

Wood Thrush

Sing a song of distance

Scientists have discovered that song birds fly much faster during their migrations than previously thought.

Purple Martin in Redmond, Washington, USA.Writing in this week's Science, York University, Canada researcher Bridget Stutchbury and her colleagues tracked the progress of two species of migrating birds, wood thrushes and purple martins.  The team trapped birds in their native Pennsylvania and equipped them with tiny geolocator backpacks.  These devices continually log light levels, allowing the position of a bird wearing one to be accurately pinpointed by referring to the sunrise and sunset times, which of course vary geographically.  Once tagged the birds were released and embarked on their winter migrations to South America.

The following year, when the birds returned to their US mating sites, the team re-captured a number of them and downloaded the data from the geo-locators, enabling the routes the birds had taken, and over what time periods, to be retraced.

"Never before has anyone been able to track songbirds for their entire migratory trip," says study author Bridget Stutchbury.  Previous estimates had put the birds' speeds at at about 93 miles (150 km) per day, but the new results show that they are covering more than three times that distance.  They were also up to six times faster returning in the spring for mating that during the outward leg when there's a competitive advantage to being the first back because early arrivals have access to the best nest sites and the most food.

Wood ThrushEven so, the researchers were surprised by the results. "We were flabbergasted by the birds' spring return times. To have a bird leave Brazil on April 12 and be home by the end of the month was just astounding.  We always assumed they left sometime in March," Stutchbury said. The researchers also found that prolonged stopovers were common during fall migration.  The purple martins, which are members of the swallow family, had a stopover of three to four weeks in the Yucatan before continuing to Brazil.  Four wood thrushes spent one to two weeks in the southeastern United States in late October, before crossing the Gulf of Mexico, and two other individuals stopped on the Yucatan Peninsula for two to four weeks before continuing migration.

This work is extremely important from a conservation perspective.  "Songbird populations have been declining around the world for 30 or 40 years, so there is a lot of concern about them," points out Stutchbury.  "Tracking birds to their wintering areas is also essential for predicting the impact of tropical habitat loss and climate change.  Until now, our hands have been tied in many ways, because we didn't know where the birds were going.  They would just disappear and then come back in the spring.  It's wonderful to now have a window into their journey."

Freshwater fish from South America and popular aquarium fish. Latin name Astronotus ocellatus. Common name Oscar. Pattern: Tiger

08:32 - The Genetic Root of All Teeth

Researchers have found the genetic root of all teeth, and it may shed some light on the evolution of feathers and fur...

The Genetic Root of All Teeth
Dr Todd Streelman,

Chris - Also in the news this week, researchers at Georgia institute of Technology in Atlanta have discovered the genetic 'root' of all teeth!

By looking at a type of fish called Cichlids, which have teeth both in the mouth and the throat, they noticed that the development of both sets of teeth is controlled by the same set of genes.  The same genes could also control the pattern of growth of feathers and hair - so could shed more light on some of the big evolutionary changes of the past.

Dr Todd Streelman, one of the authors on this week's Public Library of Science paper, joins us now...

Astronotus ocellatus. Common name Oscar.Todd - We study a very unique group of fishes from Lake Malawi in East Africa. What's so fascinating about them is that they express a tremendous diversity of all sorts of things like colour patterns and brain function and also their teeth. We were able to make use of this natural diversity to begin to ask the question about how they actually make teeth in two different places on the body. Once we found the answer to that we put this information together with lots of information in the literature to try to understand how teeth were made a long time ago and also to try to understand the things in common between all teeth that we presently know about.

Chris - What was the genetic clue that tells you where the teeth have come from in the first place?

Todd - This is one of the interesting things that many people don't know, the co-evolutionary history of teeth and jaws. Teeth first of all: about half a billion years ago they evolved in organisms that did not have jaws. Interestingly enough they evolved first in the pharynx, deep in the throat. Then they also evolved on the oral jaw, the jaw on the front of our face, when that jaw first appeared in vertebrate history. As you imagined in the fishes we studied they had teeth both on their oral jaw but they also have teeth back in this ancestral location for teeth. We used a technique called in situ hybridisation which is just a way to visualise where and when genes are active. We studied a number of molecules that we had some inkling might be involved in dentition. We identified two things. We identified this ancient set of genes and that ancient set of genes is the set of genes that's on in the pharynx when teeth are made. Secondly we identified a core set of genes. That core set represents the gene at work that's active in all teeth. From the fishes we study to shark, to mice and in your teeth as well.

Models of human teeth as they exist within the alveolar boneChris - When you study an early human embryo you can see the same vestiges as the development of a fish occurring in us, for instance. We get gills at certain stages of development too, don't we? We get these bronchial arches which, some of them, turn into things like our ear drums and out tonsils. In fish they would have been gills but superimposed on that is this pattern of genes that gives us teeth.

Todd - That's right. There's a very old rule in evolutionary biology called ontogeny recapitulates phylogenies. That just means that, in a very coarse way, if you look at a contemporary organism and look at its development you can learn something about evolutionary vestiges by studying early phases of its development. That's one of the things we take advantage of. We also were able to identify some differences between this ancestral network active in these throat teeth and the core network that's active in the oral jaw of most organisms. We think those are probably some of the genes that tell us about some of the things that have changed  as dentitions have evolved over half a billion years. For instance, in the fishes we study they replace every single tooth about every 50-100 days. This is one of these things we think - and other people have suggested also- links teeth to other structures like feathers and hairs that also have this capacity for regeneration. Your teeth are replaced a single time but other mammals never replace their teeth. These are aspects of dentition that have been lost as teeth have evolved. Some of those interesting regenerative capacities are still present in both the pharyngeal and oral teeth that we studied.

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