Sunday, June 20

The suffocation that gives wings to Alzheimer’s | Science

A patient with Alzheimer's, in a center in Dax (France) last September.
A patient with Alzheimer’s, in a center in Dax (France) last September.GONZALO FUENTES / Reuters

Alzheimer’s advances and its progression seems unstoppable. The World Health Organization (WHO) estimates that between 5% and 8% of the population over 60 years of age suffers from dementia at some point and will go from affecting 82 million people in nine years to 152 million in three decades. Alzheimer’s is the main reason for these cases and there is no cure. The study of its causes, however, opens up the hope of being able to stop it. An investigation, published in Nature Aging and led by Javier Vitorica and Alberto Pascual, from the Institute of Biomedicine of Seville (IBIS), Hispalense University, CIBERNED and CSIC, has identified a pathway that gives wings to Alzheimer’s: the hypoxia of the cells in the brain, the lack of oxygen that it affects the function of this main and little-known organ. Unraveling its functioning opens the way to treatments and the adoption of life habits that stop the disease.

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The most accepted theses in scientific research relate Alzheimer’s with the formation of beta-amyloid protein plaques (which in the laboratory for simplicity they call abetas) that cause direct toxic effects on neurons) and neurofibrillary tangles of tau protein. Chris Peers, from the University of Leeds (United Kingdom), explains that “the primary neurotoxic elements of Alzheimer’s accumulate over the years to form the extracellular plaques, which are the hallmark of the disease.” The same researcher affirms, in a work published in Essays in Biochemistry, that numerous cardiorespiratory disorders or strokes “completely deprive the brain of oxygen for a period of time and patients suffering from these conditions are much more susceptible to developing Alzheimer’s.”

Microglia is the brain’s immune system, it works by protecting it and has been shown to be deficient in Alzheimer’s patients

Javier Vitorica, researcher of the Aging and Neurodegeneration group

The new work by Vitorica and Pascual sheds a lot of light on this chain that gives wings to Alzheimer’s. According to the research, “sustained systemic hypoxia contributes to the progression of Alzheimer’s by decreasing the microglial capacity to proliferate and confine deposits of abetas ”. “Microglia is the brain’s immune system, it acts to protect it and it has been shown to be deficient in Alzheimer’s patients,” Vitorica summarizes.

The research detects three factors that open the barrier to the progression of the disease: genetic factors (such as the TREM2 gene), which “accelerate the pathology”, as Pascual explains; systemic (infections or decreased oxygen delivery to the brain due to cardiovascular accidents) and local stress (the HIF1 molecule, a factor known as 1-alpha that increases due to hypoxia). These three elements, according to the study’s conclusion, “converge in the reduction of the microglial clustering and, mainly, in its barrier function.

The beta-amyloids are like the accident at the Chernobyl nuclear power plant and the microglia is like the body of workers that came to seal it. But the stress of low oxygen levels predisposes you to not being able to defend your brain

Alberto Pascual, doctor in Biology and scientist

The activation of the microglia, that brain’s immune system, is necessary to stop neurodegeneration because, according to the study, its “cells are capable of surviving near the deposits of abetas and provide a complete answer ”. “The beta-amyloids are like the accident at the Chernobyl nuclear power plant and the microglia is like the body of workers that came to seal it. But the stress of having low oxygen levels predisposes her to not being able to defend her brain ”, Pascual exemplifies.

The HIF1 molecule is also involved in this line of defense. “Its over-activation”, according to the work, affects the proliferation and grouping capacity around the toxic plaques. “The rise in HIF1 levels compromises the mitochondrial activity of microglial cells and limits their protective capacity against disease,” the researchers argue.

Vitorica uses an example to explain: “Running a marathon requires an aerobic metabolism. If you take the oxygen out of the runner, he will not be able to cover the 42 kilometers. When the level of oxygen in the brain decreases, HIF1 increases to adapt, but ultimately cannot act and inhibits mitochondria [la parte de la célula responsable de la respiración y de la generación de energía]”

How to help microglia stop the disease

The study has been carried out by over-activating the factors involved that reduce brain oxygenation, as in the cases of hypertension, obesity, atrial fibrillation, diabetes, physical inactivity, smoking and arteriosclerosis.

This experimentation is key to the relevance of the study, since it facilitates the search for pharmacological agents that could improve the metabolic capacity of the microglia against toxic plaques and, probably, reduce the progression of the disease. But it also allows the work to identify living conditions that can affect the brain’s defense capabilities.

“We cannot change genetics, but we can act on what we know accelerates pathology, such as arteriosclerosis, cholesterol, the risks of cardiovascular accidents, obesity, diet or inactivity”, explains Alberto Pascual. This researcher highlights how in countries where vital habits have been improved, such as the United States or the United Kingdom, there has been a decrease in the incidence of the disease between 2010 and 2012. On the contrary, nations that had healthier lifestyles , like Japan, they begin to register a higher rate of the disease due to their changes in habits.

The discovery of a specific drug is still a long way off, but the progression of Alzheimer’s can be delayed with lifestyle habits

The two scientists agree that finding a specific drug is still a long way off. “The biggest problem is that you don’t know where to act from a molecular point of view,” explains Vitorica. “The workhorse is determining early markers,” adds Pascual. But they also agree that any habit that slows the progression of the disease is a huge triumph. In this sense, Vitorica points out: “It is important to maintain a socially and intellectually active life, to exercise the body and mind.” Pascual adds: “We invite you to think. Like any part of the body, the brain, the more it is used, the better ”.

The conclusions of the study coincide with those of Chris Peers regarding the importance of the association between hypoxia in the brain and the predisposition to suffer from Alzheimer’s, something that has been less studied than the pathogenic causes (the accumulation of firs). “Emerging evidence suggests that pathological cell remodeling caused by chronic hypoxia shows striking similarities to those seen in the central nervous system as a consequence of Alzheimer’s,” confirms the British researcher. “Current knowledge supports the concept that prevention of the detrimental effects of hypoxia may provide beneficial in slowing or preventing the onset of the disease,” he concludes.

Four variants of Alzheimer’s

Other research, published in Nature Medicine Y focused on the effects of the accumulation of the tau protein, it has identified four variants of Alzheimer’s depending on the brain region they affect:

Variant One: The tau protein extends primarily within the temporal lobe and affects memory. It has been identified in 33% percent of the 1,612 cases analyzed.

Variant two: the tau extends into the rest of the cerebral cortex. The individual has fewer memory problems than with the first variant, but experiences greater difficulties with the functions of planning and executing actions. It was detected in 18% of the cases.

Variant three: the accumulation of tau takes place in the visual cortex, where information from the optic nerve is processed and classified. Those affected have difficulties in orienting themselves, distinguishing shapes and contours, distances, movements and the locations of objects in relation to others. Variant three was detected in 30% percent of the individuals analyzed.

Variant four: tau spreads asymmetrically in the left hemisphere and mainly affects the individual’s linguistic ability. It was present in 19% of the cases.

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