Alzheimer’s disease: the neuroprotective potential of novel synthetic compounds targeting P-glycoprotein

Abstract

Background: Alzheimer’s disease (AD) is a progressive neurological disorder characterized by cognitive decline associated, specifically, with the degeneration of cholinergic neurons [1]. Although the etiology of the disease remains elusive, with several pathophysiological mechanisms contributing to disease progression, two main pathological hallmarks are well described, namely the presence of 1) neurofibrillary tangles formed by unfolded protein aggregates (hyperphosphorylation of tau protein) and 2) extracellular aggregates of Aβ within the brain [2, 3]. Objective: The present work aimed to perform a screening of the potential neuroprotective effects of 21 novel small molecules in a cholinergic-differentiation model of neuronal cells using the SH-SY5Y neuroblastoma cell line. Methods: SH-SY5Y cells were differentiated into a cholinergic phenotype in response to treatment of at least 7 days with retinoic acid at a final concentration of 10 μM, under low serum conditions [4, 5]. The assays selected to evaluate the potential neuroprotective effects were chosen to replicate some of the emerging disease-related hallmarks, namely: metal ion dyshomeostasis, ferroptosis and impairments in Aβ clearance [modulation of P-glycoprotein (P-gp) activity] [3, 6]. Results: The results of this study highlighted the remarkable neuroprotective effects of the majority of compounds against iron (III)- and erastin-induced cytotoxicity, in addition to their ability to modulate P-gp activity. Furthermore, the P-gp activators (compounds I-VIII, XII and XXI) were evaluated in a cellular model of AD-like pathology of Aβ-induced cytotoxicity. The obtained results demonstrated the ability of compounds to protect the differentiated cells against the toxic stimulus, implicating the ATP-dependent efflux pump - P-gp - in the clearance of Aβ aggregates. Conclusions: Thus, this study reinforces the several efforts that have been made toward counteracting AD multifactorial nature by shifting the strategy into the design of P-gp activators for preventing, delaying or treating AD.