Transient dynamics of Aβ contribute to toxicity in Alzheimer’s disease

Abstract

The aggregation and deposition of the amyloid-β peptide (Aβ) in the brain has been linked with neuronal death, which progresses in the diagnostic and pathological signs of Alzheimer’s disease (AD). The transition of an unstructured monomeric peptide into self-assembled and more structured aggregates is the crucial conversion from what appears to be a harmless polypeptide into a malignant form that causes synaptotoxicity and neuronal cell death. Despite efforts to identify the toxic form of Aβ, the development of effective treatments for AD is still limited by the highly transient and dynamic nature of interconverting forms of Aβ. The variability within the in vivo “pool” of different Aβ peptides is another complicating factor. Here we review the dynamical interplay between various components that influence the heterogeneous Aβ system, from intramolecular Aβ flexibility to intermolecular dynamics between various Aβ alloforms and external factors. The complex dynamics of Aβ contributes to the causative role of Aβ in the pathogenesis of AD.

Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes

“…In addition, given the high complexity of the fibrillation process, and considering the overall dynamics of the assembly and disassembly of toxic amyloid species, the possibility that toxicity is displayed by different conformers should not be disregarded. Moreover, it has also been suggested that the ongoing aggregation process, rather than a clearly defined aggregate, is responsible for amyloid toxicity (30,63).…”

Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-β-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer’s disease

“…Studies have supported that indanone moiety plays an important role in AChEs inhibition. 18 In addition to this, curcumin appeared as a potential Aβ aggregation inhibitor with potent antioxidant activity 19 and the piperazine scaffold is also used extensively to develop AChE inhibitors, neuroprotective as well as antioxidant molecules. 17 Thus, our designed molecules are endowed with necessary pharmacophoric features required for AChEs inhibition, Aβ aggregation inhibition, neuroprotective and antioxidant activity, which may warrant their multifunctional activity for AD.…”

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

“…Aβ1‐42 aggregates more quickly and stably than Aβ1‐40. Aβ1‐42 polymerization is believed to occur in sequential phases: First Aβ monomers aggregate into soluble oligomers that then form insoluble oligomers, generating protofibrils and fibrils (Hubin et al ., 2014). Soluble Aβ1‐42 oligomers constitute the more toxic form of the peptide (Bolmont et al ., 2007; Nimmrich & Ebert, 2009; Guglielmotto et al ., 2014).…”