Alzheimer’s is a neurodegenerative disease for which there is still no cure and which is estimated to affect around 800,000 people in our country, according to data from the Spanish Society of Neurology (SEN), which also indicates that Alzheimer’s is diagnosed every year 40,000 people. To prevent this type of dementia and develop therapies capable of stopping its progression, it is essential to know its causes.
An international team of scientists led by Spanish researchers from the Cajal Institute of the Higher Council for Scientific Research (IC-CSIC) have discovered a potential therapeutic target to target new drugs for the treatment of Alzheimer’s. Specifically, these scientists have studied the mechanism of amyloid formation in the neurotoxic protein tau, a structure whose pathological accumulation is associated with the appearance of neurodegenerative diseases such as Alzheimer’s.
The results of the study have been published in the journal Angewandte Chemie and show a possible new therapeutic target at the beginning of this biochemical cascade, which would consist of preventing tau from forming amyloid and, in this way, blocking, at a very early stage, the factors that subsequently lead to the development of these dementias.
“Our study provides new information on the mechanism of amyloid formation by tau, early in the process, relevant for future studies in search of effective therapeutic interventions against Alzheimer’s”
The tau protein is part of the cytoskeleton of cells, it is expressed above all in neurons, and is related to the correct functioning of neurons and the brain, however, tau stops fulfilling its normal function in people suffering from Alzheimer’s and it begins to form toxic amyloid aggregates inside neurons and glial cells, eventually causing their death. The reasons why this occurs are still unknown.
Tau, like most amyloid-forming proteins, presents a large conformational polymorphism in its non-aggregated form (it fluctuates between different structures or conformations). These scientists have discovered that, contrary to what happens with other neurotoxic proteins, tau needs to be partially destructured, that is, to reduce its conformational polymorphism, in order to initiate the amyloidogenic cascade related to the development of the disease.
Prevent the accumulation of amyloid to stop Alzheimer’s
The authors of the new study used a technique that allows the study of individual molecules, force spectroscopy, which is based on the use of an atomic force microscope, to analyze molecule by molecule the structure and behavior of tau before it is released. become pathological and thus discovered the first changes that initiate the process of amyloid formation. “This information opens the door to the identification of a possible ideal therapeutic target, from the pharmacological point of view, since it is at the beginning of the biochemical cascade that triggers the formation of amyloid,” said Mariano Carrión, a researcher at the IC-CSIC and research leader.
Over the past two decades, the amyloid cascade hypothesis has been the starting point of Alzheimer’s research. This hypothesis considers that the accumulation of amyloid would explain the pathological characteristics of this dementia, which include, among others, the formation of neurofibrillary tangles made up of hyperphosphorylated tau and extracellular plaques made up of beta-amyloid peptide, dysfunction of the synapse or communication of neurons and their death in the late stages of the disease.
A large part of the research whose objective is to find therapies that cure Alzheimer’s or help prevent its appearance is based precisely on this hypothesis, which is why they are looking for a way to prevent its accumulation, which is a challenge for scientists because it is not know well how this process develops.
“Our study provides new information on the mechanism of amyloid formation by tau, early in the process, relevant for future studies in search of effective therapeutic interventions, and also on the possible structural basis of the variability observed in amyloid fibers of tau. tau in different diseases”, concludes the CSIC researcher.
Researchers from the Rocasolano Institute of Chemistry-Physics (IQFR-CSIC), the University of Hong Kong and the University of Texas Southwest (United States) have also participated in the study.
Source: Cajal Institute of the Higher Council for Scientific Research (IC-CSIC)
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