Fighting Alzheimer’s disease

In just seven years, by 2030, one in five people residing in Europe and the United States will have reached 65 years of age. And by 2035, people over the age of 65 will for the first time outnumber those under the age of 18. As a consequence, the prevention of age-related diseases such as Alzheimer’s, a true invisible pandemic, is of increasing importance for the quality of life, public health and the economy.

Aging is the main risk factor for developing Alzheimer’s disease. This disease, which begins several decades before showing the first symptoms, already affects 1 in 10 people over the age of 65, a figure that increases to 3 in 10 from the age of 85.

Without effective medication that at least stops the progression of this devastating pathology, prevention becomes the best bet, for now, to reduce the incidence of the disease that Alois Alzheimer described for the first time in 1906, and which is one of the largest challenges of current medicine.

Beyond focusing on the two proteins characteristically associated with Alzheimer’s, amyloid beta and tau, a strategy that has so far met with little success, there are other modifiable factors that can be influenced. In fact, a study recently published in the academic journal PNAS indicated a 30% decrease in the number of elderly people with dementia in less than 15 years in the United States, despite the absence of effective drugs. Education and access to better healthcare appear to be behind it, presumably reducing the risk factors associated with Alzheimer’s, which partly overlap with those that increase cardiovascular risk.

Image of the brain of a mouse showing the association between blood vessels (red) and microglia (white). (Photo: Alberto Pascual (IBiS))

In 2020, another study published in the academic journal Neurology pointed in the same direction: “The incidence rate of dementia in Europe and North America has decreased by 13% per decade over the past 25 years, consistently across all countries. studies. These observations call for sustained efforts to discover the causes of this decline, as well as determine its relevance in geographically and ethnically diverse populations.”

In this line, the laboratory of the researcher Alberto Pascual, from the Higher Council for Scientific Research (CSIC) in Spain, published in 2021 an important finding on the behavior of brain blood vessels in Alzheimer’s disease, in a work carried out at the Institute of Biomedicine of Seville (IBiS), a mixed center of the CSIC, the University of Seville and the Virgen del Rocío and Macarena University Hospitals.

Published in the academic journal Nature Communications, this study led by the Pascual laboratory (CSIC), from the IBiS Neuronal Maintenance Mechanisms Group, whose first authors were María Isabel Álvarez Vergara and Alicia E. Rosales-Nieves, described a new mechanism It disrupts the blood vessels around the amyloid plaques characteristic of Alzheimer’s disease and complicates it. The study demonstrated for the first time that a problem in angiogenesis (the mechanism by which new blood vessels are produced) causes the destruction of capillaries and, therefore, a decrease in the supply of nutrients and oxygen to the brain.

Previously, in April 2021, Pascual’s group described in the academic journal Nature Aging that the brains of Alzheimer’s patients accumulate markers that are associated with poor oxygenation. To deepen this finding, the researchers set out to find out “whether this neurodegenerative disease could be directly affecting the blood vessels of the brain, which would explain the comorbidity with peripheral vascular deterioration factors and the lack of oxygen observed in the brain in patients with Alzheimer’s,” explains Pascual.

Following an analysis of previous studies on the cerebral vasculature in Alzheimer’s patients, the researchers realized that there were signals in the brain for the creation of new blood vessels, by a process called angiogenesis, but at the same time the number decreased. of functional vessels observed near the beta-amyloid (Aβ) plaques characteristic of this neurodegenerative pathology. “All this was paradoxical: the brain called for the generation of new vessels but the net result was their absence,” Pascual points out.

In this study, published in the academic journal Nature Communications, research groups from the University of Malaga (Professor Antonia Gutiérrez), the CIEN Foundation (Dr. Alberto Rábano), the Cajal Institute (Dr. Fernando de Castro), the Institute of Neurosciences of Alicante (Dr. Eloisa Herrera), the Hamburg-Eppendorf University Medical Center of Germany (Dr. Jakob Körbelin) and the IBiS (professors Javier Vitorica, Javier Villadiego and Miriam Echevarría).

They focused on a possible angiogenesis dysfunction. This mechanism is important during embryonic development to form the vessels of the brain and in adult life to recover from possible damage to pre-existing vessels. The work demonstrated that Alzheimer’s disease induces dysfunctional angiogenesis that causes the loss of vessels instead of their formation, which undoubtedly aggravates this neurodegenerative pathology.

A distinctive feature of Alzheimer’s is the accumulation in the brain of highly toxic substances, in what is known as senile plaques. Transport through the blood is one of the mechanisms for removing these toxic substances from the brain. “The fact that the plaques cause the loss of blood vessels constitutes a vicious circle: having fewer blood vessels can cleanse the brain less and accumulate more toxic substances, which in turn continue to destroy the vessels and complicate the situation in the brain affected by Alzheimer’s”, clarifies Pascual.

In addition, since the brain consumes a good part of the oxygen (20%) and the nutrients of the body, the local reduction of the supply of these substances through the blood supposes a situation of additional stress to the one already existing due to the accumulation of substances. toxic reactions that occur in Alzheimer’s disease.

The data provided by this research also linked familial Alzheimer’s, of genetic origin, with problems in the formation of new blood vessels, which highlights the importance of the vascular component in this pathology that affects more than 1,200,000 people in Spain.

As a proof of concept, the researchers led by Pascual showed that relevant improvements in the ability to memorize in models of Alzheimer’s disease occur when administering antiangiogenic treatments that are used to treat cancer. They are currently working on demonstrating the importance of recovering cerebral blood vessels in order to improve the cognitive function of people affected by this disease.

“Once the molecular pathways involved in this destructive process of blood vessels associated with Alzheimer’s disease have been identified, new therapeutic strategies can be rationally designed to alleviate the effects of this disease on the blood vessels of the brain”, Alberto highlights. Paschal. (Source: Pilar Quijada Garaballu / CSIC)