An international team led by the Cajal Institute of the Higher Council for Scientific Research (IC-CSIC), in which researchers from the Rocasolano Institute of Physical Chemistry (IQFR-CSIC), the University of Hong Kong and the University of Texas Southwest (USA), studied the mechanism of amyloid formation in the neurotoxic protein tau, a generally pathological structure that forms 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, published in the journal Angewandte Chemiereveal 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 strategy would be based on preventing tau from forming amyloid and, therefore, on blocking, at a very early stage, the subsequent stages that lead to the development of these dementias.
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 therefore 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, the scientists analyzed the structure and behavior of tau molecule by molecule before it became pathological. or non-aggregated monomer or molecular form) and discovered what are the first changes that start the process of amyloid formation.
“This information opens the door to the identification of a possible ideal therapeutic day, from the pharmacological point of view, as it is found at the beginning of the biochemical cascade that triggers the formation of amyloid”, explains Mariano Carrión, researcher at the Cajal Institute and leader of the investigation.
Using an atomic force microscope, the scientists analyzed the structure and behavior of tau, molecule by molecule, before it started to become pathological.
Like most amyloid-forming proteins, tau exhibits a large conformational polymorphism in its non-aggregated form (it fluctuates between different structures or conformations). These scientists 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.
Mechanism of amyloid formation
Over the past twenty years, the hypothesis of the so-called amyloid cascade has served as a reference in research on Alzheimer’s. According to her, the increase in amyloid would explain the pathological characteristics of the disease, which include, among others, the formation of neurofibrillary tangles formed by hyperphosphorylated tau and extracellular plaques formed by beta-amyloid peptide, dysfunction of synapses or neuron communication and its death in late stages of the disease.
Much of the research that has as its final objective the cure and prevention of Alzheimer’s is based on this hypothesis and tries to find ways to interrupt this accumulation, a process 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 looking for effective therapeutic interventions, and also on the possible structural basis of the observed variability in tau amyloid fibers. tau in different diseases”, specifies the researcher.
Mariano Carrión-Vázquez et al. “Expanded conformations of monomeric Tau initiate its amyloidogenesis. Angewandte Chemie”. Angewandte Chemie (2023)