Mitigation of amyloid aggregation and toxicity

Amyloid aggregation is associated with an increasing list of degenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and type-2 diabetes. The hallmark common to all amyloid diseases is the deposition of beta-sheet rich fibrils formed of by misfolding and aggregation of otherwise soluble proteins and peptides. Mounting experiments suggest that soluble oligomers instead of mature fibrils are more toxic. As the intrinsically transient and heterogenous intermediates of amyloid aggregation, these oligomeric species are highly elusive. In addition, not all oligomers are toxic. The objective of our research is to uncover the structure and dynamics of amyloid aggregation and focus on the early aggregation process in order to pinpoint the toxic subspecies.  In our lab, we apply multiscale molecular dynamics simulations to model the aggregation of various amyloidogenic proteins and peptides, characterize the free energy landscape of the assembly process, and identify the structural and dynamics signatures of the toxic oligomers by working closely with experimental groups. The obtained molecular and structural insights to amyloid toxicity will help better understand the disease mechanisms and aid in the design of therapeutic strategies against amyloidosis.

Our strategy of mitigating amyloid toxicity is to minimize the population of toxic oligomers and/or reduce the direct exposure of cells to these toxic species. The overall population of toxic oligomers can be reduced by stabilizing monomers, non-toxic or “off-pathway” oligomers, or accelerating the formation of non- or less-toxic fibrils. The direct cell exposure to toxic oligomers can also be achieved by caging these culprits. In our lab, we have been exploring the applications of small molecules, endogenous proteins and peptides, and engineered nanomaterials with specific physicochemical properties as amyloid-mitigating agents. For instance, we have uncovered the amyloid-mitigation mechanisms of several naturally-occurring polyphenols (e.g., resveratrol, curcumin, and EGCG) reported in the literature to be able to inhibit the aggregation of different amyloid peptides. For the aggregation of human islet amyloid polypeptide (hIAPP, aka amylin) associated with beta-cell death in type-2 diabetes, we also studied the effects of various IAPP-colocalizing molecules including insulin, zinc ion, c-peptide and hydrogen ion at low pH in the beta-cell granule, where hIAPP is stored without apparent aggregation for hours between meals at mM concentrations. In the search for anti-amyloid nanomedicine, we have been studying the physicochemical determinants of nanoparticles in mitigating amyloid aggregation and toxicity. All these research projects are highly inter-disciplinary and collaborative, and results from the synergy between simulations and experiments. Molecular modeling and dynamics simulations have been employed not only to help explain experimental characterizations and elucidate molecular mechanisms but also to make predictions and guide experimental validations.

Fig. 1 – A) The free energy landscape of amyloid aggregation as a function of the aggregation size and fraction of β‐sheet content (QFibril), obtained from computer simulations of model peptides. The landscape encompasses initial oligomerization of monomers to low β‐sheet oligomers, nucleation of β‐sheet structures in the oligomers (i.e., β‐sheet rich oligomers including β‐barrels), and their subsequent elongation into cross‐β fibrils. B) Nanomaterials have been found to reduce the population of toxic β‐sheet‐rich oligomers by stabilizing monomers (e.g., dendrimers), low β‐sheet oligomers (e.g., graphene quantum dots), or protofibrils (e.g., gold nanoparticles coated with β‐lactoglobulin amyloid fragments and poly (2‐hydroxyl ethyl acrylate) star polymers). IAPP was used as the representative peptide. GQD: graphene quantum dot. bLg‐AuNP: β‐lactoglobulin amyloid fragment.