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1. Gallium nanoparticles as novel inhibitors of Aβ40 aggregation

   https://doi.org/10.1039/D1MA00461A  

   Torres, Kyabeth M.; Delgado, Ambar S.; Serrano, Erika R.; Falcón-Cruz, Nitza V.; Meléndez, Anamaris; Ramos, Idalia; Du, Deguo; Oyola, Rolando (August 2021, Materials Advances)

   Alzheimer's disease (AD) has been consistently related to the formation of senile amyloid plaques mainly composed of amyloid β (Aβ) peptides. The toxicity of Aβ aggregates has been indicated to be responsible for AD pathology. One scenario to decrease Aβ toxicity is the development of effective inhibitors against Aβ amyloid formation. In this study, we investigate the effect of gallium nitride nanoparticles (GaN NPs) as inhibitors of Aβ40 amyloid formation using a combination of biophysical approaches. Our results show that the lag phase of Aβ40 aggregation kinetics is significantly retarded by GaN NPs in a concentration dependent manner, implying the activity of GaN NPs in interfering with the formation of the crucial nucleus during Aβ aggregation. Our results also show that GaN NPs can reduce the amyloid fibril elongation rate in the course of the aggregation kinetics. It is speculated that the high polarization characteristics of GaN NPs may provoke a strong interaction between the particles and Aβ40 peptide and in this way decrease self-association of the peptide monomers to form amyloids. 

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2. Pathways of amyloid-beta absorption and aggregation in a membranous environment

   https://doi.org/10.1039/C9CP00040B  

   Sahoo, Abhilash; Xu, Hongcheng; Matysiak, Silvina (April 2019, Physical Chemistry Chemical Physics)

   Aggregation of misfolded oligomeric amyloid-beta (Aβ) peptides on lipid membranes has been identified as a primary event in Alzheimer's pathogenesis. However, the structural and dynamical features of this membrane assisted Aβ aggregation have not been well characterized. The microscopic characterization of dynamic molecular-level interactions in peptide aggregation pathways has been challenging both computationally and experimentally. In this work, we explore differential patterns of membrane-induced Aβ 16–22 (K–L–V–F–F–A–E) aggregation from the microscopic perspective of molecular interactions. Physics-based coarse-grained molecular dynamics (CG-MD) simulations were employed to investigate the effect of lipid headgroup charge – zwitterionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phosphocholine: POPC) and anionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phospho- l -serine: POPS) – on Aβ 16–22 peptide aggregation. Our analyses present an extensive overview of multiple pathways for peptide absorption and biomechanical forces governing peptide folding and aggregation. In agreement with experimental observations, anionic POPS molecules promote extended configurations in Aβ peptides that contribute towards faster emergence of ordered β-sheet-rich peptide assemblies compared to POPC, suggesting faster fibrillation. In addition, lower cumulative rates of peptide aggregation in POPS due to higher peptide–lipid interactions and slower lipid diffusion result in multiple distinct ordered peptide aggregates that can serve as nucleation seeds for subsequent Aβ aggregation. This study provides an in-silico assessment of experimentally observed aggregation patterns, presents new morphological insights and highlights the importance of lipid headgroup chemistry in modulating the peptide absorption and aggregation process. 

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3. Molecular insights into the surface-catalyzed secondary nucleation of amyloid-β ₄₀ (Aβ ₄₀ ) by the peptide fragment Aβ _16–22

   https://doi.org/10.1126/sciadv.aav8216  

   Bunce, Samuel J.; Wang, Yiming; Stewart, Katie L.; Ashcroft, Alison E.; Radford, Sheena E.; Hall, Carol K.; Wilson, Andrew J. (June 2019, Science Advances)

   Understanding the structural mechanism by which proteins and peptides aggregate is crucial, given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of Aβ 40 and Aβ 16–22 , two widely studied peptide fragments of Aβ 42 implicated in Alzheimer’s disease. We demonstrate that Aβ 16–22 increases the aggregation rate of Aβ 40 through a surface-catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between Aβ 40 monomers/oligomers on the surface of preformed Aβ 16–22 fibrils nucleate Aβ 40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly. 

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4. Mechanistic insights into the inhibition of amyloid-β aggregation by chitosan

   https://doi.org/10.1039/D3CP00162H  

   Gotla, Suhas; Matysiak, Silvina (April 2023, Physical Chemistry Chemical Physics)

   Neurodegeneration related to Alzheimer's disease has long been linked to the accumulation of abnormal aggregates of amyloid-β (Aβ) peptides. Pre-fibrillar oligomeric intermediates of Aβ aggregation are considered the primary drivers of neurotoxicity, however, their targetting remains an unresolved challenge. In response, the effects of macromolecular components of the blood–brain barrier, artificial extracellular matrix mimics, and polymeric drug delivery particles, on the aggregation of Aβ peptides are gaining interest. Multiple experimental studies have demonstrated the potential of one such macromolecule, chitosan (CHT) – a polysaccharide with acid induced cationicity (p K a 6.5) – to inhibit the aggregation of Aβ, and reduce the associated neurotoxic effects. However, the mechanistic details of this inhibitory action, and the structural details of the emergent Aβ complexes are not understood. In this work, we probed how CHT modulated the aggregation of Aβ's central hydrophobic core fragment, K 16 LVFFAE 22 , using coarse-grained molecular dynamics simulations. CHT was found to bind and sequester Aβ peptides, thus limiting their ultimate aggregation numbers. The intensity of this inhibitory action was enhanced by CHT concentration, as well as CHT's pH-dependent degree of cationicity, corroborating experimental observations. Furthermore, CHT was found to reshape the conformational landscapes of Aβ peptides, enriching collapsed peptides at near-physiological conditions of pH 7.5, and extended peptides at slightly acidic conditions of pH 6.5, where the charge profile of K 16 LVFFAE 22 peptides remained unchanged. These conformational changes were limited to peptides in direct contact in CHT, thus emphasizing the influence of local environments on Aβ conformations. These findings add to basic knowledge of the aggregation behaviour of Aβ peptides, and could potentially guide the development of advanced CHT-based materials for the treatment of Alzheimer's disease. 

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5. Cross-seeding between Aβ and SEVI indicates a pathogenic link and gender difference between alzheimer diseases and AIDS

   https://doi.org/10.1038/s42003-022-03343-7  

   Tang, Yijing; Zhang, Dong; Zhang, Yanxian; Liu, Yonglan; Miller, Yifat; Gong, Keven; Zheng, Jie (May 2022, Communications Biology)

   Abstract Amyloid-β (Aβ) and semen-derived enhancer of viral infection (SEVI) are considered as the two causative proteins for central pathogenic cause of Alzheimer’s disease (AD) and HIV/AIDS, respectively. Separately, Aβ-AD and SEVI-HIV/AIDS systems have been studied extensively both in fundamental research and in clinical trials. Despite significant differences between Aβ-AD and SEVI-HIV/AIDS systems, they share some commonalities on amyloid and antimicrobial characteristics between Aβ and SEVI, there are apparent overlaps in dysfunctional neurological symptoms between AD and HIV/AIDS. Few studies have reported a potential pathological link between Aβ-AD and SEVI-HIV/AIDS at a protein level. Here, we demonstrate the cross-seeding interactions between Aβ and SEVI proteins using in vitro and in vivo approaches. Cross-seeding of SEVI with Aβ enabled to completely prevent Aβ aggregation at sub-stoichiometric concentrations, disaggregate preformed Aβ fibrils, reduce Aβ-induced cell toxicity, and attenuate Aβ-accumulated paralysis in transgenic AD C. elegans. This work describes a potential crosstalk between AD and HIV/AIDS via the cross-seeding between Aβ and SEVI, identifies SEVI as Aβ inhibitor for possible treatment or prevention of AD, and explains the role of SEVI in the gender difference in AD. 

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