Multitarget Neuroprotective Effects of Quercetin on the Pathogenesis of Amyloid-β_1-42 in Alzheimer’s Disease: In-vitro and In-silico study

¹ School of Pharmacy, Faculty of Medicine and Health Science, Universitas Muhammadiyah Yogyakarta, Kampus Terpadu UMY Jl. Brawijaya, Kasihan, Bantul, Daerah Istimewa Yogyakarta 55183.
² School of Medical Laboratory Technology, Poltekkes Kemenkes Yogyakarta, Jl. Tata Bumi No.3, Banyuraden, Gamping, Sleman, Daerah Istimewa Yogyakarta 55293

^* Corresponding author: puguh.arsito@gmail.com

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and neuronal death. The pathophysiology of AD includes cholinergic nerve damage, neuroinflammation, oxidative stress, and misfolding of amyloid-beta protein (Aβ). Current AD drug development focuses on a single target, whereas the AD mechanism is multifactorial, originating from the Aβ cascade, so intervention in Aβ is necessary. Flavonoid compounds are known to have many neuroprotective activities. Quercetin, an easily found flavonoid, can be used against AD. This research aimed to evaluate quercetin’s neuroprotective effect in inhibiting AD progression. In the in-vitro test, quercetin was assessed for its impact on inhibiting monomeric Aβ1-42 aggregation and inducing the disintegration of Aβ1-42 fibrils. Quercetin was also evaluated for its toxicity on differentiated human cholinergic cells (SH-SY5Y). Next, the neuroprotective effect of quercetin was tested in the same cells as Aβ1-42 induction. In-silico methods (Molecular docking and Molecular dynamics) were carried out to explain the molecular mechanism of drug action. In addition, druglikeness and ADMET parameters of flavonoids were predicted using SwissADME and pKCSM software. Quercetin is known to have a dual effect as an inhibitor of monomeric Aβ1-42 aggregation and a disintegrator of Aβ1-42 fibrils at concentrations of 10 µM – 200 µM. In molecular docking analysis, it is known that quercetin can bind to the hydrophobic part of Aβ1-42. Tests using molecular dynamics increasingly confirm that quercetin can disrupt the stability of Aβ1-42. In cell culture tests, quercetin was found to have a neuroprotective effect at an effective dose of 1-10 µM. ADMET parameters can also predict Quercetin and fulfill the Lipinski-Veber rule for predicting drug-likeness parameters. Quercetin has the potential to be developed as an anti-Alzheimer’s drug candidate with multi-target activity in the Aβ cascade.