Protein aggregates

See through the tangle

Protein aggregates in

Protein aggregates are clusters of misfolded proteins in the form of oligomers, tangles, plaques, and fibrils. A wide range of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS), are associated with the formation and accumulation of toxic aggregates, progressive neuronal dysfunction, and cell death.  

However, it has been a challenge to characterize the aggregates and their interaction with drug candidates. Pathogenic oligomeric or fibrillar forms of proteins can be large, heterogenous, varied in shape, size, and stability, making it difficult for sample preparation and measurement. 

How can we help?

We built our Fluidity One-M instrument with your challenges in mind. Our proprietary Microfluidic Diffusional Sizing (MDS) technology enables in-solution measurements of proteins in their native environment, while the smart assistant – Fluidity Insight – with advanced machine learning experiment guidance, will ensure you’re always on the right path.

True size

Measure the size of the complex to understand its state, formation, stability & interactions with other molecules.

True environment

Measure in-solution without immobilization. Works in native environments like crude cell lysate and cerebrospinal fluid.

True insights

Calculate stoichiometry of interaction with monomers, oligomers and fibrils intuitively using standardized models.

Application Note

In solution measurement of antibody affinities and binding stoichiometries to neurotoxic amyloid species

Learn how we utilize MDS to measure size, affinity and stoichiometry of protein complexes formed by antibodies and amyloid oligomers or fibrils.

True size

By measuring the size of ganglioside lipid particles alone and in the presence of amyloid β peptide using Microfluidic Diffusional Sizing, Hu et al. demonstrated the binding of amyloid peptide to lipid particles at low µM concentrations. The study “shed light on glycolipid–peptide interactions that may play an important role in Alzheimer’s pathology”.

Read more from the original article.

True environment

Microfluidic Diffusional Sizing tackles protein interactions directly in biofluids. In this example, it was used to detect binding of an anti-synuclein nanobody to synuclein species in cell lysate. Binding to disordered monomeric a-synuclein was also distinguished from binding to fibrils due to the technology’s ability to determine the size in solution of the particle of interest.

Read more from the original article.

True insights

The mode of action of the FDA-approved anti-Alzheimer’s disease therapeutic aducanumab was elucidated using Microfluidic Diffusional Sizing. This study revealed that aducanumab is able to coat the sides of amyloid β fibrils, and thereby shut down the self-amplifying secondary nucleation process. Previously unsuccessful therapeutic candidates bapineuzumab and gantenerumab were found to bind the ends of fibrils while solanezumab sequesters monomeric amyloid β.

Read more from the original article.

Explore related publications

Study the mechanism of action of anti-Aβ antibodies

Linse et al. combine kinetic analyses with MDS binding measurements to address the mechanism of action of four clinical stage anti-Aβ antibodies. They quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Their results reveal that only one of these four antibodies dramatically reduces the flux of Aβ oligomers which is linked to its inhibitory potential.

Linse, Sara, et al. “Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies.” Nature structural & molecular biology 27.12 (2020): 1125-1133.

Investigate the behavior of αSyn-LiPs in αSyn aggregation assays

Falke et al. utilized MDS as one of the methods to investigate the role of α-synuclein-derived lipoparticles in the formation of α-synuclein (αSyn) amyloid fibrils, which are implicated in the pathology of Parkinson’s disease. The study suggested αSyn-lipid particles can effectively induce, accelerate or inhibit αSyn aggregation, depending on the applied conditions.

Falke, Marcel, et al. “α-Synuclein-derived lipoparticles in the study of α-Synuclein amyloid fibril formation.” Chemistry and physics of lipids 220 (2019): 57-65.

Science that empowers science

MDS allowed us to obtain unique information that helped us elucidate, for the first time, the way antibody therapeutics bind to different forms of their targets.

Sara Linse

Professor, Lund University

Fluidic Sciences Ltd