Gold Nanoparticles as a Probe for Amyloid‑β Oligomer and Amyloid Formation

The process of amyloid-β (Aβ) amyloid formation is pathologically linked to Alzheimer’s disease (AD). The identification of Aβ amyloids and intermediates that are crucial players in the pathology of AD is critical for exploring the underlying mechanism of Aβ aggregation and the diagnosis of the disease. Herein, we performed a gold nanoparticle (AuNP)-based study to detect the formation of Aβ amyloid fibrils and oligomers. Our results demonstrate that the intensity of the surface plasmon resonance (SPR) absorption band of the AuNPs is sensitive to the quantity of Aβ40 amyloids. This allows the SPR assay to be used for detection and semiquantification of Aβ40 amyloids and characterization of the kinetics of Aβ amyloid formation. Furthermore, our study demonstrates that the SPR band intensity of the AuNPs is sensitive to the presence of oligomers of Aβ40, and an Aβ40 mutant which forms more stable oligomers. The kinetics of the stable oligomer formation of the Aβ40 mutant can also be monitored following the SPR band intensity change of AuNPs. Our results indicate that this nanoparticle-based method can be used for mechanistic studies of early protein self-assembly and fibrillogenesis

Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139:1157

The insulin/insulin growth factor (IGF) signaling (IIS) pathway is a key regulator of aging of worms, flies, mice, and likely humans. Delayed aging by IIS reduction protects the nematode C. elegans from toxicity associated with the aggregation of the Alzheimer’s disease-linked human peptide, Ab. We reduced IGF signaling in Alzheimer’s model mice and discovered that these animals are protected from Alzheimer’slike disease symptoms, including reduced behavioral impairment, neuroinflammation, and neuronal loss. This protection is correlated with the hyperaggregation of Ab leading to tightly packed, ordered plaques, suggesting that one aspect of the protection conferred by reduced IGF signaling is the sequestration of soluble Ab oligomers into dens

Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity

SummaryFibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-beta and alpha-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation, and autophagy. Our results suggest that MOAG-4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases

Morphology and dynamics of star dunes from numerical modelling

International audienceStar dunes are giant, pyramid-shaped dunes composed of interlaced arms. These arms are marked by sinuous crests and slip faces of various directions. Their radial symmetry and scale suggest that the star dunes form as a result of complex interactions between a multidirectional wind regime and topography. However, despite their ubiquity in modern sand seas, comparatively little is known about their formation and evolution. Here we present a discrete numerical model of star-dune behaviour based on the feedback mechanisms between wind flow and bedform dynamics. Our simulations indicate that the morphology of star dunes results from the combination of individual longitudinal dunes. We find that the arms of the star dunes propagate only under favourable wind regimes. In contrast to dunes that form from an erodible bed, the crests of the propagating arms are oriented such that sand flux is maximized in the direction of arm growth. Our analysis of the simulated three-dimensional structures suggests that the morphodynamics of the arms are controlled by the frequency of wind reorientation, with a high frequency of reorientation leading to smaller arm dimension and high rates of growth. We suggest that arm propagation is an important process of mass exchange in dune fields