Scientists have studied the mechanism of amyloid formation in the neurotoxic protein tau, a usually pathological structure that is formed from a biochemical cascade of structural changes and that accumulates in the brain of patients suffering from neurodegenerative diseases such as Alzheimer’s. The results reveal a possible new therapeutic target at the beginning of this biochemical cascade, which would be based on preventing tau from forming amyloid and, therefore, on blocking, at a very early moment, the subsequent steps that lead to the development of these dementias.
The research is the work of an international team led by the Cajal Institute (IC) of the Higher Council for Scientific Research (CSIC) in Spain. Researchers from the Rocasolano Institute of Chemistry-Physics (IQFR), attached to the CSIC, have participated in the team. And experts from the University of Hong Kong in China and the University of Texas Southwest in the United States have also intervened.
Tau is an intrinsically disordered protein (it does not adopt a single three-dimensional structure, like most of them) that is part of the cytoskeleton of cells and is expressed mainly in neurons. It belongs to the family of microtubule-associated proteins and may be related to axonal transport and growth, neuronal polarization, and thus the normal functioning of neurons and the brain. In patients affected by Alzheimer’s disease, tau stops fulfilling its normal function for reasons still unknown and begins to form toxic amyloid aggregates inside neurons and glial cells, which eventually cause their death.
Using a technique that allows the study of individual molecules called force spectroscopy, based on the use of an atomic force microscope, scientists have analyzed the structure and behavior of tau on a molecule-by-molecule basis before it becomes pathological. (in the simplest or non-aggregated monomer or molecular form) and have discovered what are 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,” says Mariano Carrión, IC researcher and leader of the investigation.
Like most amyloid-forming proteins, tau presents in its non-aggregated form a large conformational polymorphism (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.
Artist’s rendering of neurofibrillary tangles and brain cells affected by Alzheimer’s disease. (Illustration: Amazings/NCYT)
The biochemical cascade
In the last twenty years, the hypothesis of the so-called amyloid cascade has served as a reference in Alzheimer’s research. According to her, the increase in amyloid would explain the pathological characteristics of the disease, which include, among others, the formation of neurofibrillary tangles made up of hyperphosphorylated tau and extracellular plaques made up of beta-amyloid peptide, synapse dysfunction or communication of neurons and their death in late stages of the disease.
Much of the research that has as its ultimate goal the cure and prevention of Alzheimer’s is based on this hypothesis and tries to find ways to interrupt this accumulation, a process that is not yet fully understood by scientists.
“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”, specifies Carrión.
The study is titled “Expanded Conformations of Monomeric Tau Initiate Its Amyloidogenesis. And it has been published in the academic journal Angewandte Chemie. (Source: Alda Ólafsson / CSIC)