Proliferation of Tau 304-380 Fragment Aggregates through Autocatalytic Secondary Nucleation.

The self-assembly of the protein tau into neurofibrillary tangles is one of the hallmarks of Alzheimer's disease and related tauopathies. Still, the molecular mechanism of tau aggregation is largely unknown. This problem may be addressed by systematically obtaining reproducible in vitro kinetics measurements under quiescent conditions in the absence of triggering substances. Here, we implement this strategy by developing protocols for obtaining an ultrapure tau fragment (residues 304-380 of tau441) and for performing spontaneous aggregation assays with reproducible kinetics under quiescent conditions. We are thus able to identify the mechanism of fibril formation of the tau 304-380 fragment at physiological pH using fluorescence spectroscopy and mass spectrometry. We find that primary nucleation is slow, and that secondary processes dominate the aggregation process once the initial aggregates are formed. Moreover, our results further show that secondary nucleation of monomers on fibril surfaces dominates over fragmentation of fibrils. Using separate isotopes in monomers and fibrils, through mass spectroscopy measurements, we verify the isotope composition of the intermediate oligomeric species, which reveals that these small aggregates are generated from monomer through secondary nucleation. Our results provide a framework for understanding the processes leading to tau aggregation in disease and for selecting possible tau forms as targets in the development of therapeutic interventions in Alzheimer's disease.

Kinetic fingerprints differentiate the mechanisms of action of anti-Aß antibodies.

The amyloid cascade hypothesis, according to which the self-assembly of amyloid-ß peptide (Aß) is a causative process in Alzheimer's disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aß-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-Aß antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We 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 Aß. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aß oligomers.

Nanoplastics formed during the mechanical breakdown of daily-use polystyrene products.

Large amounts of plastics are released into the environment every day. These released plastics have a clearly documented negative effect on wildlife. Much research attention has been given to large plastic pieces and microplastics. However, if the breakdown of plastics is a continous process, eventually nanoplastics will be produced. Nanoplastics will affect wildlife differently from larger plastic pieces. We have studied the products formed by the mechanical breakdown of two commonly used polystyrene products, takeaway coffee cup lids and expanded polystyrene foam. After breakdown using a food processor, we characterized the breakdown products using seven different methods and found nanosized polystyrene particles with different shapes and negative or nearly neutral surface charges. These results clearly demonstrate that daily-use polystyrene products can break down into nanoparticles. Model polystyrene particles with different sizes and surface modifications have previously been shown to have different negative effects on wildlife. This indicates that breakdown nanoparticles might have the potential to cause cocktail effects in nature.