Introduction

Amyloid-β (Aβ) is the trigger of the devastative and progressive procedure of Alzheimer’s disease (AD) pathological cascade as a prominent neurodegeneration disease (Chiu et al. 2015). Aβ transport and metabolism are two aspects of the clearance pathway involved in diminishing the toxicity impact. In the transporting aspect, low-density lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end-products (RAGE) have two contradicting functions in the blood–brain barrier (BBB), in which LRP1 participates in the efflux of Aβ from interstitial fluid (Cai et al. 2018). LRP1, in addition to transporting, has multiple functions for which its deletion causes early embryonic lethality (Shinohara et al. 2017). In contrast, RAGE inhibition has not depicted any fatality in the case of inhibition, thus becoming a candidate target for develo** novel AD medications (Cui et al. 2017). Above all, P-glycoprotein (P-gp) is highlighted as a modulator of AB-level in the BBB (Mohamed et al. 2016). In addition to the Aβ transporting aspect, it is worth mentioning β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which involves in the amyloidogenic pathological pathway (Huang et al. 2021).

Since statins have less BBB penetration rate, they cannot influence neurons and their products in CNS. Moreover, they have a less binding affinity toward different forms of Aβ, except for silymarin which can bind to Aβ1-40 (not toxic) and Aβ fibril (toxic). In contrast, studies suggested administration of statins could attenuate Aβ accumulation (Bai et al. 2019; Mohamed et al. 2016). To explain this paradox, we could highlight Aβ receptors which most of the statins can bind to them efficiently. Statins strongly bind to RAGE, P-glycoprotein, ABCA1, and ACE2. These receptors interact with Aβ and are known to involve in its transport and clearance. In vitro studies conceptualize the extracellular V domain of (RAGE) as a key domain for ligand binding (Singh and Agrawal 2022; Tolstova et al. 2022; Yue et al. 2022). Our results also confirm this prediction and as depicted in Fig. 1, all compounds bind to this domain as the best confirmation (Fig. 1). However, the MD simulation contradicts these results. To explain this conflict, it is worthwhile to note that the RAGE receptor is attached to the membrane of cells. Hence, its interaction with other membrane compounds results in protein structure alternation. Therefore, since the complex system of membrane proteins is hard to simulate, in this study, just a simplified condition was simulated. ACE expressed by the endothelium and its action is mainly thought to be a mediator for salt balance. Nonetheless, its inhibition through small molecules was stated to prevent Aβ aggregation (** et al. 2021; Le et al. 2021). Our result finds out the high binding affinity of statins to ACE2, and it may facilitate Aβ binding for peripheral clearance.

Another important finding of this study is quercetin’s tumorigenic and mutagenic properties. Multiple studies declared the anti-tumor properties of quercetin and highlighted its role in eliminating tumors (Rauf et al. 2018; Reyes-Farias and Carrasco-Pozo 2019; Shafabakhsh and Asemi 2019; Tang et al. 2020). Its exact mechanism has not been clearly discovered; nevertheless, it is suggested to act through various mechanisms like regulating PI3K/Akt/mTOR, Wnt/-catenin, and MAPK/ERK1/2 pathways (Reyes-Farias and Carrasco-Pozo 2019) or promoting cytotoxic effects. However, Shafabakhsh et al. declare that it did not affect healthy cells (Shafabakhsh and Asemi 2019), and its mutagenic properties must be assessed through various methods. Quercetin may affect cells by inducing DNA mutation, and because cancer cells have high DNA transcription, it can affect them with a higher effect than healthy cells.

Duan et al. conducted research on APP/PS1 transgenic mice with administration of 200 mg/kg silybin once a day for 28 days, and its effect was measured in vitro and in vivo. The results revealed a decline in AChE activity (Duan et al. 2015). This research outcome acknowledges our results that show silymarin and most of the statins have high binding affinity and can inhibit AChE.

As far as β-secretase known as BACE1 has a proven high impact on cleavage and metabolism of amyloid-beta precursor protein in multiple studies (Hampel et al. 2021), new biosynthesis medicine should be focused on inhibition of this enzyme. None of the compounds analyzed in our study has a high potential effect for inhibiting this enzyme. To put all the results together, our studies suggested the potential inhibitory effects of selected ligands on hallmark proteins involved in AD pathological symptoms; nevertheless, their efficiency could be improved by designing effective nanoparticles to transport and penetrate BBB, which help to increase the bioavailability of mentioned ligands in the CNS. Moreover, one of the limitations of our study is the implementation of in vitro and in vivo assessment; therefore, further in vivo and in vitro studies are needed to fully confirm the influence of the mentioned ligands on selected receptors and prove the role of statins on amyloidogenesis pathway with involvement of RAGE, ACE2, and P-gp.

Conclusion

Memory impairment as a neurological and neurophysiological phenomenon influences patients’ life quality. Aβ accumulation as one of the factors which influence memory can be diminished through multiple treatment strategies. RAGE as a receptor transporting Aβ into the CNS and P-gp as a crucial mediator in Aβ signaling can be efficiently inhibited by statins as well as silymarin. AChE can be inhibited by quercetin more effectively than donepezil. In addition, statins can affect other proteins, including amyloid precursors like protein 2, ACE2, and TNF-α. The pharmacokinetic properties of statins and antioxidants reveal their ability to peripheral clearance of Aβ since they have a poor BBB penetration rate. Also, some of them (further study needed) including atorvastatin and quercetin may have a low ability to ameliorate the reproductive system failure and tumorigenicity.