Foldamer-Mediated Structural Rearrangement Attenuates Aβ Oligomerization and Cytotoxicity

Abstract

The conversion of the native random coil amyloid beta (Aβ) into amyloid fibers is thought to be a key event in the progression of Alzheimer's disease (AD). A significant body of evidence suggests that the highly dynamic Aβ oligomers are the main causal agent associated with the onset of AD. Among many potential therapeutic approaches, one is the modulation of Aβ conformation into off-pathway structures to avoid the formation of the putative neurotoxic Aβ oligomers. A library of oligoquinolines was screened to identify antagonists of Aβ oligomerization, amyloid formation, and cytotoxicity. A dianionic tetraquinoline, denoted as 5, was one of the most potent antagonists of Aβ fibrillation. Biophysical assays including amyloid kinetics, dot blot, ELISA, and TEM show that 5 effectively inhibits both Aβ oligomerization and fibrillation. The antagonist activity of 5 toward Aβ aggregation diminishes with sequence and positional changes in the surface functionalities. 5 binds to the central discordant α-helical region and induces a unique α-helical conformation in Aβ. Interestingly, 5 adjusts its conformation to optimize the antagonist activity against Aβ. 5 effectively rescues neuroblastoma cells from Aβ-mediated cytotoxicity and antagonizes fibrillation and cytotoxicity pathways of secondary nucleation induced by seeding. 5 is also equally effective in inhibiting preformed oligomer-mediated processes. Collectively, 5 induces strong secondary structure in Aβ and inhibits its functions including oligomerization, fibrillation, and cytotoxicity.

Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers

“…Collectively, we termed this process aggregation, catalyzed by interaction with the surfaces. Aggregates can dissociate from the surface and initiate disease-related effects via different pathways [7,[36][37][38][39][40][41][42], including interference with recently identified mitochondrial protein biogenesis [43,44] and neuronal hyperactivation at the prodromal state of the disease [4]. Notably, our model is focused on the very early stages of amyloid aggregation, which represent the early onset of disease.…”

Structure Elucidation of Helical Aromatic Foldamer–Protein Complexes with Large Contact Surface Areas

“…Some possess antibiotic activity . Both linear and helical foldamers have been developed and varied targets have been identified, including h DM2 and B‐cell lymphoma‐2 (Bcl‐2) regulator proteins, protein precursors of amyloids,– G‐quadruplex DNA and some DNA‐binding enzymes . Advantages of aromatic foldamers include their ease of synthesis, for example through solid‐phase methodologies, and the predictability and stability of their folded conformations in both protic and aprotic solvents .…”

Alleviation of symptoms of Alzheimer's disease by diminishing Aβ neurotoxicity and neuroinflammation

“…7 Since Ab aggregation and its neurotoxicity could be aggravated by metal ions such as Zn 2+ and Cu 2+ in the AD brain, 8,9 metal chelators that can regulate the distribution of metal ions are potential therapeutic agents for AD. 10,11 Extensive studies have focused on the reduction of Ab or its aggregation by targeting Ab production or clearance, [12][13][14][15] and some compounds have effectively prevented the de novo aggregation of Ab; however, they cannot eliminate the existing Ab oligomers and plaques in the brain. 16 Consequently, such strategies hardly improve the cognition of patients, and none of them have gone through clinical trials so far.…”