The risk of age-related Alzheimer's disease explained at the molecular level

Studies have shown that the incidence of Alzheimer's disease increases with age. This badociation with age also correlates with abnormal tau protein deposits in the brain, according to a new study. Susanne Wegmann and colleagues at the German Center for Neurodegenerative Diseases (DZNE) in Berlin, in close collaboration with researchers at US Harvard Medical School and Mbadachusetts General Hospital, worked on laboratory animals to prove that folding and depositing Abnormal tau in specific regions of the brain (entorhinal cortex of young and elderly mice) was related to AD. Their study entitled "Experimental Evidence of Tau Protein Dependence in the Brain by Age, "Was published in the last issue of the journal Progress of science. The experiments were conducted in Bradley Hyman's laboratory at Harvard Medical School in Boston, USA.

Alzheimer's disease (AD) is a progressive dementia that begins with a decline in memory and then alters cognitive abilities. The risk of developing an AD depends on age and is rarely detected before the age of 50. The incidence increases gradually with age and more than half of the population is affected by the age of 90 years. There are two types of proteins that are deposited in the brain and cause the disease. These are "amyloid beta plaque" and "neurofibrillary entanglement of tau protein". The deposition and progressive spread of "tau neurofibrillary tangles" are responsible for the progression of the disease, as they first deposit in memory centers and then spread along the nerves to the heart. other areas of the brain. The correlation between age and the incidence of AD has been attributed to these proteins that spread more easily in the aging brain.

For this new study, the team worked with young and old mice. In the region of the entorhinal cortex of these animals, they used gene vectors carrying viral molecules to cause tau protein deposits. These tau proteins were "immuno-labeled", which allowed the team of researchers to examine them closely during the experiment. Factors affecting the propagation of tau proteins, such as the age of the animal, the specific region of the brain and the misfolding of the tau protein, were evaluated. The team explains that tau protein exists in two variants: a healthy form dissolved in neurons and a diseased form that comes in the form of fibrils and aggregates. Wegmann said in a statement: "It has long been thought that it was mainly the pathological form of tau that pbaded from one cell to another. However, our results show that the healthy version of the protein is also spreading in the brain and that this process increases with age. The cells could also be damaged by receiving and accumulating large amounts of healthy tau. "

Vectors were programmed to make tau protein and injected into the mouse brain. The researchers then investigated its spread using processes such as immunostaining and flow cytometry. Until now, scientists have been able to examine only tau deposits and not its propagation in the brain, in folded and misfolded states. This study was a step forward in the study of misfolded tau proteins in the brain of laboratory animals.

To badyze the dependence of the spread of tau protein and its misfolding as a function of age, young mice aged 3 months and older (22-24 months) received an injection of tau into the entorhinal cortex ( THIS).

The results revealed detectable dissemination in the hippocampus and adjacent cortex. Over a 12-week period, there was greater spread of tau protein in the mice. This corroborates the initial hypothesis that as the brain ages, it becomes fertile ground for a faster spread of tau protein. There were also many tau folding defects that led to its faster spread, the researchers write.

In the older EC, the team noted a three-fold higher amount of tau protein. The reason behind this has not been clearly understood. The researchers hypothesized that in older mice, the spread of tau protein would be faster and the folding and accumulation of proteins increased. The team also hypothesized that there could be damage to the DNA in the cells, which could explain the tau accumulation and its folding.

In addition, the team noted that tau protein accumulated more in areas such as EC, but was not grouped in the same way in the striatum region of the brain. The researchers speculate that this could be due to the differences between cells and neurons that influence the transmission as well as the misfolding of proteins.

One notable finding is that misfolded tau proteins do not develop typical neurofibrillary tangles as early as non-misfolded tau proteins. This meant that the propagation of tau protein and its agglutination and aggregation were two different phenomena and were thus influenced by a distinct set of factors. The authors explain that tau molecules can spread without bending badly and that tau folding is not essential for tau propagation. They conclude: "In complex in vivo conditions, neurons appear to be able to maintain tau in an unfolded, non-aggregated state, which reinforces the possibility of a potential therapeutic window, in which one could stop the spread the pathology of tau protein by targeting the spread of tau protein regardless of its conformational state. "