With an aging population, neurological conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and stroke affect millions worldwide, with projections suggesting a steep rise of cases by 2050. While some of these conditions are treatable, many remain without a cure. Neuroprotection - preserving the structure and function of neurons amidst ongoing damage - relies on a deep understanding of pathological processes, like protein aggregation and inflammation.
Over the years scientists have attempted to reduce protein aggregation, control oxidative stress, and manage neuroinflammation. However, these approaches often fall short due to the brain’s complex architecture, which makes it challenging to replicate in the lab. Both animal models and 3D cultures that try to mimic the pathological brain environment can take months - or years! - of work to prepare. The disruptive nature of many traditional techniques means that they often offer only limited insights. Moreover, the dynamic nature of neurodegenerative processes means that by the time symptoms appear, the underlying damage may have been ongoing for years. In this context, a method to visualize these changes in real time without disrupting the sample is invaluable - this is where Amytracker steps in.
Amytracker offers a non-disrupting imaging solution to track toxic protein buildup in live neurons and animal models. By serving as a sensitive biomarker for drug testing, it enables researchers to evaluate treatment efficacy continuously, without the need to halt or disturb the experiment.
Amytracker highlights how some pathological aggregation begins within liquid-like condensates. Paolo Arosio’s team described how RNA accelerates the aggregation of phase-separated hnRNPA1A, a protein linked to ALS, in an in vitro model. Similarly, Leonard Piroska and colleagues showed that phase-separated α-synuclein, a protein implicated in PD pathology, is more prone to aggregation than its soluble forms - suggesting that the increased concentration within these condensates might initiate the early events of pathological protein buildup.
Many phase-separated condensates are formed by the cell in response to stress, either to protect certain macromolecules from damage or to quickly arrest non-essential processes in order to redirect energy towards stress-mitigating ones. Timothy Audas and his team discovered that, in response to stress, cells form reversible amyloid bodies, which include some disease-associated proteins, and may trigger the aggregation observed in neurodegenerative disease such as ALS and AD. Their findings, shared during a recent webinar, highlighted that while some compounds that inhibit aggregation in vitro prove ineffective in live cells, drugs like diclofenac show more promise, by preventing the inclusion of β-amyloid into these bodies. Amytracker was also central to the work of Luca Pinzi, Christian Conze, and their colleagues, who developed a live-cell imaging assay to test compounds for preventing tau aggregation. This innovative platform led to the identification of PHOX15 as capable of restoring the interaction between microtubules and tau, thereby halting further aggregation.
Overall, these advances underscore the pivotal role of Amytracker in enhancing our understanding of neurodegenerative diseases and refining the testing of potential treatments. By allowing researchers to monitor pathological changes in real time, Amytracker deepens our insights into the early events of neurodegeneration, paving the way for the development of more effective neuroprotective strategies.
Image: Under pathological conditions, neurons accumulate stress-induced, phase-separated condensates (shown in red), which can act as hotspots for toxic protein aggregation—a key feature of many neurodegenerative diseases. Amytracker, a non-invasive imaging tool, binds selectively to these structures in live neurons, enabling real-time visualization without disrupting the cellular environment. This enables the evaluation of drug candidates that aim to prevent or reverse aggregation, offering a valuable tool in the development of neuroprotective therapies.
Read More:
- Steinmetz, J. D. et al (2024) Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 23(4):344-381
- Feigin V.L. et al (2020) The global burden of neurological disorders: translating evidence into policy. Lancet Neurol. 2020 Mar;19(3):255-265.
- Chandhok, S., Pereira, L., Momchilova, E.A. et al. (2023) Stress-mediated aggregation of disease-associated proteins in amyloid bodies. Scientific Reports, 13, 14471.
- Morelli, C., Faltova, L., Capasso Palmiero, U. et al. (2024) RNA modulates hnRNPA1A amyloid formation mediated by biomolecular condensates. Nature Chemistry, 16, 1052–1061.
- Piroska, L et al. (2023) α-Synuclein liquid condensates fuel fibrillar α-synuclein growth. Science Advances, 9(33), eadg5663
- Pinzi, L. et al. (2024) Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction. Nature Communications, 15(1), 1679