Inhibition of Amyloid β-Induced Lipid Membrane Permeation andAmyloid β Aggregation by K162.

Dusan Mrdenovic,Izabela S Pieta,Piotr Pieta,Piotr Zarzycki,Robert Nowakowski,Marta Majewska,Wlodzimierz Kutner,Jacek Lipkowski

doi:10.1021/acschemneuro.0c00754

Abstract

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration associated with amyloid β (Aβ) peptide aggregation. The aggregation of Aβ monomers (AβMs) leads to the formation of Aβ oligomers (AβOs), the neurotoxic Aβ form, capable of permeating the cell membrane. Here, we investigated the effect of a fluorene-based active drug candidate, named K162, on both Aβ aggregation and AβO toxicity toward the bilayer lipid membrane (BLM). Electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM), and molecular dynamics (MD) were employed to show that K162 inhibits AβOs-induced BLM permeation, thus preserving BLM integrity. In the presence of K162, only shallow defects on the BLM surface were formed. Apparently, K162 modifies Aβ aggregation by bypassing the formation of toxic AβOs, and only nontoxic AβMs, dimers (AβDs), and fibrils (AβFs) are produced. Unlike other Aβ toxicity inhibitors, K162 preserves neurologically beneficial AβMs. This unique K162 inhibition mechanism provides an alternative AD therapeutic strategy that could be explored in the future.

Highlights

Alzheimer’s disease (AD), the most prevalent type of dementia,[1] is a fatal, neurodegenerative disorder that leads to a cognitive impairment such as memory loss, communication difficulties, and personality changes
These Electrochemical impedance spectroscopy (EIS) features are observed for the bilayer lipid membrane (BLM) in the absence of Aβ oligomers (AβOs) and K162 (Figures S1a and S1b)
The only remaining kind of amyloid β (Aβ) aggregates formed in the K162 presence is nontoxic Aβ fibrils (AβFs), which adsorb on the BLM surface without destroying it,[10,11] and they cannot insert into neurons.[35]

Summary

INTRODUCTION

Alzheimer’s disease (AD), the most prevalent type of dementia,[1] is a fatal, neurodegenerative disorder that leads to a cognitive impairment such as memory loss, communication difficulties, and personality changes. Aβ aggregates via nucleation-dependent polymerization in which Aβ monomers (AβMs) associate into Aβ oligomers (AβOs) and Aβ fibrils (AβFs).[2−4] Recent studies consider AβOs to be the most toxic form, while AβMs and AβFs are considered nontoxic.[5−7] AβOs can permeate the cell membrane,[8−12] and once incorporated into the cell, AβOs can cause learning and cognition deficiency,[13,14] deterioration of synapses,[15,16] leakage of lysosomal enzymes,[17] inhibition of mitochondrial activity,[18] increased production of reactive oxygen species,[19] and neuroinflammation.[20,21]. In the K162-modified Aβ aggregation, AβMs dimerize These Aβ dimers (AβDs) do not oligomerize but fibrillate.

RESULTS AND DISCUSSION

CONCLUSIONS

MATERIALS AND METHODS

■ ACKNOWLEDGMENTS

■ REFERENCES