Implications of peptide assemblies in amyloid diseases

Abstract

Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology – much of which are poorly understood – these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer’s, Parkinson’s, type 2 diabetes and prions diseases. In addition, we discuss the toxicities of these amyloid proteins based on their self-assembly as well as their interactions with membranes, metal ions, small molecules and engineered nanoparticles. Through this presentation we show the remarkable similarities and differences in the structural transitions of the amyloid proteins through primary and secondary nucleation, the common evolution from disordered monomers to alpha-helices and then to β-sheets when the proteins encounter the cell membrane, and, the consensus (with a few exceptions) that off-pathway oligomers, rather than amyloid fibrils, are the toxic species regardless of the pathogenic protein sequence or physicochemical properties. In addition, we highlight the crucial role of molecular self-assembly in eliciting the biological and pathological consequences of the amyloid proteins within the context of their cellular environments and their spreading between cells and organs. Exploiting such structure-function-toxicity relationship may prove pivotal for the detection and mitigation of amyloid diseases.

Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation

“…Aggregation inhibition with the use of small molecules as well as metal, carbon, and polymeric nanoparticles (NPs) 6−9 has been a major strategy against amyloid-mediated toxicity. Polymeric NPs, specifically, have been explored as protein aggregation inhibitors utilizing their tunable hydrophobicity as well as their capacity for initiating H-bonding.…”

Cofibrillization of Pathogenic and Functional Amyloid Proteins with Gold Nanoparticles against Amyloidogenesis

“…1, 2 Although much progress has been made in the past decades towards understanding the molecular and mesoscopic structures of protein fibrils as well as their fibrillization kinetics and toxicity, there is a crucial lack of strategies for probing the aggregation of amyloid proteins in situ , despite their relevance to elucidating the pathologies of amyloid diseases and to the development of effective theranostics. 1, 3 …”

Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide

“…Aggregation of proteins and peptides into amyloid fibrils is implicated in many human diseases 1 , including amyloid-β (Aβ) in Alzheimer’s disease (AD) 2–4 , α-synuclein in Parkinson’s disease 5 , prion protein in the prion disease 6, 7 , and islet amyloid polypeptide (IAPP, a.k.a. amylin) in type 2 diabetes mellitus (T2D) 8–10 .…”