How does Alzheimer's begin?
Swedish scientists shed light on the early stage of Alzheimer's disease
LifeSciencesToday based on the materials of Karolinska Institutet: New light shed on early stage Alzheimer's diseasePart of the process leading to the death of neurons in Alzheimer's disease is a violation of the metabolism of sugars, fats and calcium.
Scientists at the Karolinska Institute, Sweden, have shown for the first time how important organelles of a nerve cell involved in its energy metabolism function at an early stage of this disease. Their somewhat unexpected results shed light on the connection of Alzheimer's disease with the metabolism of neurons.
Plaques consisting of beta-amyloid accumulate in the brain of patients with Alzheimer's disease. It is also well known that the neurons of the brain of such patients are characterized by metabolic disorders, in particular, glucose and calcium, directly related to cell death. Mitochondria are responsible for the metabolism of these substances – the power plants of the cell that provide it with energy.
Damage to a neuron by beta-amyloid in Alzheimer's disease. (Fig. National Institute on Aging/NIH)However, in order to perform their function, mitochondria need good contact with another part of the cell – the endoplasmic network, or endoplasmic reticulum (ER). A specialized area of the endoplasmic reticulum in contact with mitochondria is called the MAM region (mitochondrial-associated membranes).
Previous studies on yeast and other cell types have shown that deactivation of certain proteins in the MAM region destroys the points of contact between mitochondria and ER, preventing the supply of energy to the cell and causing its death.
Scientists at the Karolinska Institute studied the MAM region of neurons and investigated the interaction between mitochondria and ER at an early stage of Alzheimer's disease. Although beta-amyloid does not form large plaques at this point in the development of the disease, the symptoms of the disease are already showing, implying a toxic effect of beta-amyloid on neurons.
The results obtained by the researchers can be called amazing. Exposure of cells to low concentrations of beta-amyloid leads to an increase in the number of contacts between mitochondria and ER, which increases the intake of calcium ions into them. As a result, excessive accumulation of calcium has a toxic effect on mitochondria and affects their ability to provide neurons with energy.
"If we want to develop molecules that stop Alzheimer's disease, we need to understand what causes the death of neurons," says study leader Maria Ankarcrona, a researcher at the Department of Neuroscience of Care Sciences and Society and the Alzheimer's Research Center of the Karolinska Institute. "In the long term, we may be able to obtain a drug that can stop the progression of the disease at a stage when the patient is still able to lead a normal daily life. To extend this period of life for several years would be a great success. Today we do not have drugs that affect the pathological process as such."
Experiments were conducted on mice with models of Alzheimer's disease, on nerve cells of patients who died from this disease, and on neurons cultured in the laboratory.
Article by Hedskog et al. Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models is published in Proceedings of the National Academy of Sciences.
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