15 April 2013

Alzheimer's disease: the missing link found

One of the main secrets of Alzheimer's disease has been revealed

LifeSciencesToday based on the materials of The Scripps Research Institute:
Scripps Research Institute Scientists Help Unravel a Central Mystery of Alzheimer’s DiseaseScientists at The Scripps Research Institute (TSRI) have shed light on one of the main mechanisms of the development of Alzheimer's disease.

Their recently published study deepens the understanding of the possible causes of this neurodegenerative disease and offers new approaches to the development of drugs for its treatment.

The results of the study published in the journal Neuron (The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Abeta Oligomers through Tau Phosphorylation) show that brain damage in Alzheimer's disease is associated with excessive activation of the enzyme AMPK (adenosine monophosphate-activated protein kinase, adenosine monophosphate-activated protein kinase). Blocking AMPK in mice with a model of this disease protects neurons from the loss of synapses – points of intercellular contacts – characteristic of the early stage of Alzheimer's disease. (The image of the model of the enzyme molecule is from the website wikipedia.org .)

"Our results open up many new directions in research, including the possibility of developing drugs that target overlying mechanisms that lead to increased activation of AMPK in the brain," says the head of the study, TSRI Professor Franck Polleux.

Alzheimer's disease is an incurable neurodegenerative disease that affects more than 25 million people worldwide. Today, medicine is not able not only to cure these patients, but even to delay the development of the disease or at least delay its onset.

As Professor Field notes, in addition to the importance for the further development of drugs, the data obtained by his group indicate the need for a deeper study of the safety of the drug metformin. Today it is believed that the mechanism of action of metformin – the most commonly prescribed antidiabetic agent – consists in the activation of the AMRK enzyme.

Scientists have long known that patients with early-stage Alzheimer's disease have a loss of synapses in certain memory-related areas of the brain. Synapse loss has always been associated with small aggregates of beta-amyloid protein, but exactly how this happens has remained a mystery.

Until recently, Professor Pohl's laboratory was not studying Alzheimer's disease, but the normal development and growth of neurons. In 2011, he and his colleagues reported that in animals, activation of AMPK by metformin, along with other compounds, negatively affects the ability of neurons to form axons.

Around the same time, several research groups received data confirming that AMPK may also play a role in the development of Alzheimer's disease. One of the groups reported that AMPK in neurons can be activated by beta-amyloid, which, in turn, leads to modification of tau protein during its phosphorylation. It is known that tangles of so-called hyperphosphorylated tau with several phosphate groups accumulate in the neurons of Alzheimer's-affected areas of the brain. This paper published two years ago reported abnormally high levels of activated AMPK in neurons containing tau tangles.

Professor Field decided to find out whether the interaction of AMPK with beta-amyloid and tau can actually lead to brain damage characteristic of Alzheimer's disease.

"Very little was known about the function of this AMRK pathway in neurons, and it so happened that we had all the tools necessary to study it," the scientist says.

Most of the experiments of the new study were conducted by Georges Mairet-Coello, a postdoctoral fellow in the laboratory of Professor Paul. He began by confirming that beta-amyloid in the form of small aggregates (oligomers) toxic to synapses does significantly activate AMPK: beta-amyloid oligomers stimulate certain neuronal receptors, which, in turn, causes calcium ions to enter cells. The intake of calcium activates the enzyme CAMKK2, which appears to be the main activator of neuronal AMPK.

The researchers then showed that AMPK hyperactivation in neurons is a key cause of beta-amyloid damage to synapses. As a rule, the addition of beta-amyloid oligomers to the culture of neurons leads to the rapid disappearance of a large number of dendritic spines – membrane outgrowths on the surface of dendrites capable of forming synapses to receive signals from other neurons. In a number of tests, scientists have shown that without increased activation of AMRK, beta-amyloid oligomers do not cause loss of dendritic spines, while activation of AMRK itself can lead to such an effect.

For the key experiment, a strain of genetically modified J20 mice with increased synthesis of mutant beta-amyloid was used, which eventually develop a condition close to Alzheimer's disease.

"Already at the age of three months, J20 mice have a significant decrease in the density of dendritic spines in a number of memory–related neurons that are also affected at an early stage of human Alzheimer's disease," Mere-Coelho comments. "But by blocking the activity of CAMKK2 or AMPK in these neurons, we completely prevented the loss of spikes."

The signal path of the AMRK (Fig. clincancerres.aacrjournals.org )Then the scientists investigated the role of the tau protein.

Usually tau performs the function of a structural element in axons, but in Alzheimer's disease, the protein is hyperphosphorylated and drifts to other areas of neurons, including dendrites, where its presence is associated with the loss of spines. Recent studies have shown that the toxic effect of beta-amyloid on dendritic spines largely depends on the presence of tau, but how exactly these two proteins interact remained unclear.

Experiments conducted in 2004 on fruit flies of fruit flies showed that phosphorylation of AMPK-like enzymes of certain tau sites leads to a cascade of further phosphorylation and degeneration of nerve cells. The experiments of Mere-Coelho and his colleagues confirmed that one of these sites, S262, is indeed phosphorylated by AMPK and that it is this phosphorylation of tau that largely determines the synaptic toxicity of beta-amyloid.

"Blocking phosphorylation by S262 in the mutant form of tau, which cannot be phosphorylated at this site, suppresses the toxic effect of beta-amyloid on the density of spikes," explains Mere-Coelho.

This result indicates that beta-amyloid contributes to the development of Alzheimer's disease through AMPK, mainly as a factor contributing to the toxicity of tau.

Currently, Professor Field and his colleagues are continuing experiments to determine which other toxic processes, such as excessive autophagy, are supported by excessive activation of AMPK and may contribute to the long-term aspects of the development of Alzheimer's disease. They are also interested in the long-term effects of blocking increased AMPK activation in the mouse model J20, as well as in other mouse models of Alzheimer's disease, which are characterized by the development of cognitive impairment at later stages of the disease.

"We have already established contacts with the pharmaceutical industry, which is potentially interested in targeting either CAMKK2 or AMPK," concludes Professor Field.

Portal "Eternal youth" http://vechnayamolodost.ru15.04.2013

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