Alzheimer's disease: two new targets

An important mechanism underlying Alzheimer's disease has been discovered

LifeSciencesToday http://www.lifesciencestoday.ru / based on the materials of the Salk Institute for Biological Studies:
Salk scientists and colleagues discover important mechanism underlying Alzheimer's disease

Alzheimer's disease affects more than 26 million people worldwide. According to forecasts, by 2050, when the "baby boom" generation grows old - and this is almost 106 million people – a giant rise in morbidity is expected. Fortunately, scientists are making some progress in therapy. Cooperation between several scientific centers, including the Salk Institute for Biological Studies and the Sanford-Burnham Medical Research Institute, has allowed us to identify one of the key mechanisms of the progression of Alzheimer's disease, which gives hope that the newly modified drug will justify the expectations there are hopes for him.

In one of his previous studies, in 2009, Stephen Heinemann, professor of the Laboratory of Molecular Neurobiology at the Salk Institute, showed that Alpha7 nicotine receptors may be involved in the onset of Alzheimer's disease.

"Previous studies have revealed a possible interaction between Alpha-7 nicotine receptors (alfa7Rs) and beta-amyloid, a toxic protein contained in the characteristic feature of this disease – plaques," says Gustavo Dziewczapolski from Professor Heinemann's laboratory. "We have shown for the first time, in vivo, that the interaction of these two proteins, alfa7Rs and beta-amyloid, provokes in mice the manifestation of symptoms similar to those observed in Alzheimer's disease."

In an article in The Journal of Neuroscience, American scientists reported the results of studying mice with induced Alzheimer's disease with and without the gene encoding alfa7Rs. The researchers found that while plaques developed in both types of mice, the disorders associated with Alzheimer's disease only occurred in animals expressing alfa7Rs.

But these results have not yet given an answer to the question why this interaction leads to such an effect.

In a recent article in the Proceedings of the National Academy of Sciences (M. Talantova et al., A-beta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss), Professor Heinemann and his colleagues from the Sanford-Burnham Medical Research Institute report that they found the answer in unexpected interactions between neurons and other brain cells.

Interneuronal communication occurs through the transmission of electrical and chemical signals through synapses. One of the signaling chemicals is glutamate, an excitatory neurotransmitter that is essential for learning and memorization. When properly balanced, glutamate is part of the normal functioning of synapses. But neurons are not the only brain cells capable of secreting glutamate. This neurotransmitter is also released by astrocytes, previously considered only an interneuronal "glue".

Astrocytes in the mouse hippocampus. (Photo: sciencellonline.com )The results of the new study suggest the existence of a signaling cascade in which beta-amyloid activates alpha-7 nicotine receptors, which causes astrocytes to release an additional amount of glutamate into the synapse, overloading it with excitatory signals.

In turn, the release of glutamate activates another set of receptors outside the synapse, called extrasynaptic-N-methyl-D-aspartate receptors (extrasynaptic-N-methyl-D-aspartate receptors, eNMDARs), suppressing synaptic activity. Unfortunately, eNMDARs seem to unnecessarily suppress synapse functions, which leads to confusion and memory loss associated with Alzheimer's disease.

Now that scientists have finally identified the stages of this destructive pathway, the good news is that a drug developed in the laboratory of Stuart Lipton, MD, PhD, NitroMemantine, a modification of an earlier Memantine, can block the participation of eNMDARs in this cascade.

"Thanks to the joint efforts of our colleagues and collaborators, we finally seem to have a clear mechanistic connection between the key target of beta-amyloid in the brain – Alpha7 nicotine receptors – causing the subsequent detrimental effects associated with the onset and progression of Alzheimer's disease," says Dziewtshapolski. "This is a clear demonstration of the importance of fundamental biomedical research. Drug development is impossible without knowledge of the details of interactions at the molecular and cellular level. Our study has identified two potential targets, alfa7Rs and eNMDARs, of future drugs that we hope will increase the effectiveness of the treatment of patients with Alzheimer's disease."

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