Search

Molecular chaperones are recognized to interfere with protein aggregation, yet the underlying mechanisms are largely unknown. Here, the authors develop a kinetic model that reveals the variety of distinct microscopic mechanisms through which molecular chaperones act to suppress amyloid formation.

Amyloid fibril formation from amyloid-beta peptides is a key feature of Alzheimer’s disease, yet the mechanisms of its spatial and temporal spread remain unclear. Here, the authors reveal that amyloid-beta 42 aggregation propagates via diffusion of oligomers in solution, highlighting these species as key drivers of the spatial spreading of aggregation.

Through local pH buffering, biomolecular condensates can expand the optimal pH interval for enzymatic reactions, increasing robustness to changes in solution pH and enabling network reactions with enzymes that require different pH conditions.

Here the authors analyze material properties and aging of active phase-separated condensates by Differential Dynamic Microscopy. Arrested states are promoted by structured RNA. Low-complexity domains and biochemical reaction keep the droplets fluid-like.

Polygenic risk scores for Alzheimer’s disease derived from individuals of European ancestry can show improved performance in multiancestry settings after incorporating genome-wide association summary statistics from diverse populations.

Open compartments, termed biomolecular condensates, are involved in cellular reactions. This Comment highlights their ability to enhance robustness and control of reactions in space and time, going beyond mere acceleration or inhibition. They enable reaction engineering at the mesoscale, not just by altering concentrations but also by modifying the local environment.

The underlying mechanism for how heterotypic protein–RNA interactions modulate the liquid to amyloid transition of hnRNPA1A, a protein involved in amyotrophic lateral sclerosis, has so far remained elusive. Now characterization of hnRNPA1A condensate formation and aggregation in vitro reveals that the RNA/protein stoichiometry affects the molecular pathways leading to amyloid formation.

Here, the authors show that biomolecular condensates can enhance enzymatic rates by creating distinct solvent environments compared to the surrounding solution, and this emergent property can manifest within assemblies as small as nanometers.

Understanding of the molecular mechanisms underlying the maturation of protein condensates into amyloid fibrils associated with neurodegenerative diseases has so far remained elusive. Now it has been shown that in condensates formed by the low-complexity domain of the amyotrophic lateral sclerosis-associated protein hnRNPA1, fibril formation is promoted at the interface, which provides a potential therapeutic target for counteracting aberrant protein aggregation.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Here the authors apply machine learning approaches to Alzheimer’s genetics, confirm known associations and suggest novel risk loci. These methods demonstrate predictive power comparable to traditional approaches, while also offering potential new insights beyond standard genetic analyses.

Extracellular vesicles are being explored for various biomedical applications, but face challenges with regard to isolation, characterization and manufacturing. This Review delineates the physico-chemical landscape of extracellular vesicles to identify the distinct challenges associated with the manufacturing and isolation of extracellular vesicles from biofluids and suggests opportunities to address them.

Aβ peptide aggregation is associated with Alzheimer's disease, and Aβ fibrils can catalyze formation of toxic oligomers. Molecular chaperone Brichos binds to the fibril surface, inhibiting the catalytic cycle in vitro, and limits Aβ toxicity.

A proteome-wide thermal profiling study of osmolyte action on E. coli and human proteins within the cellular milieu reveals mechanisms of protein thermal stabilization by osmolytes and in situ behavior of intrinsically disordered proteins.

β-cell dysfunction in type 2 diabetes is associated with pathological aggregates of IAPP that accumulate in pancreatic islets. Here, the authors describe a novel antibody cloned from healthy elderly donors that selectively targets IAPP oligomers and protects from IAPP toxicity.

Labelling biomolecules to improve the sensitivity of analysis can perturb their interactions. Now, microfluidic and chemical tools have been used to allow simple, sensitive detection of a labelled system to reveal the behaviour of the native and physiologically relevant unlabelled system. The system was used to characterize the solution-phase behaviour of a clinically relevant protein–protein interaction.

Large-field multifocal illumination fluorescence microscopy and panoramic volumetric multispectral optoacoustic tomography can be combined to longitudinally assess amyloid-β deposits in transgenic mouse models of Alzheimer’s disease.

Aβ42 oligomers are key toxic species associated with protein aggregation; however, the molecular pathways determining the dynamics of oligomer populations have remained unknown. Now, direct measurements of oligomer populations, coupled to theory and computer simulations, define and quantify the dynamics of Aβ42 oligomers formed during amyloid aggregation.

The realization that the cell is abundantly compartmentalized into biomolecular condensates has opened new opportunities for understanding the physics and chemistry underlying many cellular processes¹, fundamentally changing the study of biology². The term biomolecular condensate refers to non-stoichiometric assemblies that are composed of multiple types of macromolecules in cells, occur through phase transitions, and can be investigated by using concepts from soft matter physics³. As such, they are intimately related to aqueous two-phase systems⁴ and water-in-water emulsions⁵. Condensates possess tunable emergent properties such as interfaces, interfacial tension, viscoelasticity, network structure, dielectric permittivity, and sometimes interphase pH gradients and electric potentials^6–14. They can form spontaneously in response to specific cellular conditions or to active processes, and cells appear to have mechanisms to control their size and location^15–17. Importantly, in contrast to membrane-enclosed organelles such as mitochondria or peroxisomes, condensates do not require the presence of a surrounding membrane.

Julie Williams, Michael Owen and colleagues report staged follow-up and meta-analyses of genome-wide association studies for Alzheimer's disease from the GERAD+ consortium. They identify common variants at ABCA7 and MS4A6A/MS4A4E associated with Alzheimer's disease and support for several additional susceptibility loci.

While antibodies have a remarkable track record in therapeutics, achieving sufficient specificity remains an issue. This Review discusses the physicochemistry of non-specificity, with a focus on surface patches as a key challenge, and outlines future opportunities to improve protein binding.

Understanding the mechanism of amyloid formation (protein aggregation) is important for developing treatments for many neurodegenerative diseases. Amylofit is a program for determining mechanisms and rates from protein aggregation kinetics.