The missing link
A link between two markers of Alzheimer's disease has been found
Polina Loseva, N+1
British scientists have managed to figure out how the accumulation of beta-amyloid outside of neurons causes the aggregation of tau protein inside them. It turned out that the mediator between them is the norepinephrine receptor on neurons: binding to it, beta-amyloid causes phosphorylation of tau, which then sticks together into lumps. This probably explains why Alzheimer's drugs aimed at combating beta-amyloid have proved ineffective. The work was published in the journal Science Translational Medicine (Zhang et al., β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3ß/tau cascade).
The two main tools of Alzheimer's disease are beta-amyloid and tau-protein – molecules that form extracellular and intracellular aggregates, respectively, and lead to the death of neurons. Both types of aggregates invariably accompany Alzheimer's disease, but exactly how they are related to each other is still unclear. It is known, for example, that beta-amyloid somehow provokes the accumulation of tau in cells. But considering that it accumulates outside of them, and tau is present only inside, it can be assumed that there is some special mechanism by which the amyloid transmits a signal inside the cell.
A group of researchers led by Qin Wang from The University of Alabama at Birmingham studied how the disease affects noradrenergic neurons, which degenerate in its early stages. Scientists have found that in the brains of people who died from Alzheimer's disease, compared with controls (people with healthy brains who died for other reasons), α 2A AR receptors work much more actively on these cells (p < 0.01). They perceive the neurotransmitter norepinephrine, which transmits a signal in adrenergic neurons and is responsible for the response to stress, including arousal and aggression.
The scientists decided to reproduce their observations on model mice. Despite the fact that mice do not suffer from Alzheimer's disease, they can cause similar symptoms and accumulation of beta-amyloid in the nervous tissue. And in these mice, too, α 2A AR receptors worked more actively than in ordinary animals: they reacted more strongly to the same doses of norepinephrine (p < 0.01). At the same time, the number of receptors on their cells was the same as in the control.
Therefore, the researchers suggested that beta-amyloid somehow acts on these receptors. By labeling both molecules with fluorescent dyes, they actually found that beta-amyloid is located on the cell surface next to the receptor. Moreover, it selectively bound only to this type of receptor, ignoring other adrenergic receptors.
Then the researchers checked which signal beta-amyloid transmits inside the cell. By measuring the activity of different kinase transmitters of the signal, they found that GSK3 kinase works the most intensively. In addition, under the action of beta-amyloid, phosphorylated tau protein began to accumulate in the cells - a form that precedes the aggregation of tau and the formation of destructive lumps. When GSK3 was selectively switched off, tau phosphorylation did not occur. So scientists have confirmed that beta-amyloid acts through adrenoreceptors on GSK3, which triggers the phosphorylation of tau. When the adrenoreceptors were blocked, most of the effects of beta-amyloid were reversed: GSK3 did not work, tau was not phosphorylated, and the mice even improved cognitive functions – for example, they were almost twice as fast to get out of the water on a dry platform.
Thus, scientists have built a "bridge" between two proteins of Alzheimer's disease: it turned out that beta-amyloid uses the stress signaling system for its own purposes, causing the accumulation of aggregates inside the cell. In addition, this finding may explain why most drugs against Alzheimer's disease have so far been ineffective. Many of them are designed to destroy beta-amyloid, but even in small concentrations it is enough to trigger pathological processes in neurons.
Portal "Eternal youth" http://vechnayamolodost.ru