Navigating the Sea of Amyloid Ensembles using Fluorescent Sensors

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative disorders exhibiting increasing prevalence, particularly in older populations. While age is a primary risk factor for these disorders (over 60 years old), the younger population is still vulnerable to AD and PD, especially in cases of early-onset development and genetic predispositions. Both diseases are associated with the formation of insoluble protein aggregates, known as amyloids, in the brain that builds up between neuronal cells, disrupting cell signaling functions.  

 Presently, radiodiagnostic techniques are the gold standard for in vivo imaging of amyloids, but these methods do not have sensitivity to the type of amyloid present, and are not able to provide robust data on the concentrations of these amyloids. To tackle this issue our Centre Investigator Liz New and Associate Investigator Dr Amandeep Kaur, led a team including alumna Dr Natalie Trinh and affiliate PhD student Kaustubh Bhuskute and Centre Investigator Kate Jolliffe, to develop new fluorescent-based sensors that could differentiate among clusters of amyloid fibrils with the added advantage of selectively picking out amyloids in complex mixtures, such as brain homogenates. There is potential for this work to expand towards identifying amyloids in plasma and cerebrospinal fluids. 

In this research, a series of biochemical experiments and studies in mouse models were conducted to exemplify the utility and selectivity of coumarin-based sensors. Successfully, the sensors were able to differentiate amongst the different types of amyloid fibrils in the screening, including the Aβ40, Aβ42, and Tau4R fibrils, which are involved in amyloid-related neurodegenerative disorders. In addition, the method successfully discriminated between different levels of amyloids in brain homogenate samples in AD mice models. This information is useful because amyloid plaque tends to accumulate over time, therefore the assay enables researchers to identify the progression of AD in the brain.   

The coumarin pharmacophore used in this work offers a versatile and simple model for medicinal chemists to design unique fluorescence imaging tools for the identification of amyloid plaques. The combination of the coumarin-based sensors holds potential for future development as a next-generation diagnostic tool for the detection of early-onset amyloid-related pathologies.  

 Citation:  Trinh, N., Bhuskute, K.R., Varghese, N.R., Buchanan, J.A., Xu, Y., McCutcheon, F.M., Medcalf, R.L., Jolliffe, K.A., Sunde, M., New, E.J. and Kaur, A., A Coumarin-Based Array for the Discrimination of Amyloids, 2024, ACS Sensors,  615 

 Doi: 10.1021/acssensors.3c01334 

 CIPPS contributors: Amandeep Kaur, Liz New, Kate Jolliffe, Natalie Trinh, Kaustubh Bhuskute