Amyloids are a family of proteins responsible for different biological functions, which present particular difficulties for their study. Although they are usually in a soluble state, it is known that under certain conditions they tend to clump together, leading to fibrous structures. These fibrillar structures, arising from the union of long amyloid chains, are key in the development of different disorders and, in fact, have already been related to the initial phase of different neurodegenerative diseases - such as Alzheimer's or Parkinson's.
One of the best known members of this family is beta-amyloid. Scientists have extensively studied its characteristics in recent years, since the accumulation of this protein in certain regions of the brain is one of the hallmarks of Alzheimer's disease. Not surprisingly, there is a theory known as the amyloid cascade hypothesis, which proposes that the mere transition of beta-amyloid proteins from their soluble state to the new fiber structure is an indicator of the Alzheimer's onset.
Understanding the mechanism of aggregation of these proteins (in other words, finding out how, when and why these proteins "decide" to aggregate) is one of the main research objectives in the area. However, nowadays the study of this phenomenon remains extremely complex, mainly due to the dynamic nature of the process: the first aggregates (that is, the first oligomers or 'amyloid chains' that arise in the initial stages of neurodegenerative pathologies), are very small and therefore difficult to detect.
Not the only one
Beta-amyloid is not the only protein related to neurodegenerative diseases: there is another soluble protein in the brain called alpha-synuclein, whose aggregation has also been linked to the onset of Parkinson's disease. As in the case of amyloids, the first oligomers that are formed as a result of the clumping of alpha-synuclein are unstable and very changing aggregates, which make them very difficult to detect.
At present, the main research efforts are focused on the detection of the first clusters of both protein families; a priority objective and not at all minor, since it could lead to the early diagnosis of these devastating diseases.
Warning signs at early stages
To date, the chemical approach to detect amyloid protein clustering in the brain has focused on the use of sensors based on fluorescent organic molecules (such as thioflavin), which increase their brightness when inserted into the accumulated protein. However, these fluorescent sensors only emit with the ideal intensity when the protein is already in a very advanced state of aggregation, while the pathology precursors (the fibers and the smallest clusters) go unnoticed.
Now, a team of researchers from the CiQUS (Singular Center for Research in Biological Chemistry and Molecular Materials of the University of Santiago de Compostela) composed of Dr. Ghibom Bhak and Dr. Javier Montenegro, in collaboration with Rice University (Houston, Texas, USA) has created new fluorescent metal sensors for the early detection of the first aggregates of proteins linked to Alzheimer's (beta-amyloid) and Parkinson's (alpha-synuclein) diseases.
The new rhenium and ruthenium compounds attach to the disease precursors (the amyloid oligomers), and from there they amplify at the supramolecular level a key signal known as fluorescence anisotropy. This physical phenomenon, which occurs when the emitted light varies in intensity depending on its polarization axis, allows small amyloid aggregates to be detected long before they accumulate, thus avoiding a late diagnosis in advanced stages of the disease. The article is the result of an international collaboration led by Professor Angel Martí at Rice University in Houston, and has just been published in the prestigious Journal of the American Chemical Society (JACS).
For Javier Montenegro, leader of the CiQUS group that has validated the new compounds on the Parkinson-related protein (α-synuclein), the value of this work is twofold: «it not only presents new organometallic compounds for the early detection of amyloid aggregates, but also proposes a new conceptual approach to the detection of the problem,” he says.
The new strategy uses a property of the aggregates that had not been explored until today, thus encouraging the potential development of new sensors and methods among the scientific community. As Javier Montenegro points out, «tackling this problem through fluorescence anisotropy means betting on a new approach for early diagnosis, because it allows us to detect much earlier the formation of an anomaly that could be related to very important pathological conditions».
Monitoring the Formation of Amyloid Oligomers Using Photoluminescence Anisotropy
Bo Jiang, Amir Aliyan, Nathan P. Cook, Andrea Augustine, Ghibom Bhak, Rodrigo Maldonado, Ashleigh D. Smith McWilliams, Erick M. Flores, Nicolas Mendez, Mohammad Shahnawaz, Fernando J. Godoy, Javier Montenegro, Ines Moreno-Gonzalez, and Angel A. Martí. Journal of the American Chemical Society DOI: 10.1021/jacs.9b06966