Fighting off oxidative stress, cells are equipped with antioxidant defense systems, comprising antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), and non-enzymatic antioxidants, such as glutathione and ascorbate. Dietary consumption of natural compounds can also strengthen the cellular antioxidant defense system through their adaptogenic potential [45]. Natural compounds can also target signaling pathways, including Nrf2/heme oxygenase-1 (HO-1), and thereby, potentiate intrinsic defense system [46]. Marine sterols were shown to protect against oxidative injury in various experimental models through their antioxidant property. Fucosterol and two other sterols, 3,6,17-trihydroxy-stigmasta-4,7,24(28)-triene and 14,15,18,20-diepoxyturbinarin, isolated from Pelvetia siliquosa protected against carbon tetrachloride (CCl₄)-induced oxidative stress by enhancing SOD, CAT, and GPx1 levels in CCl₄-challenged rats [20]. Fucosterol isolated from Eisenia bicyclis inhibited ROS production in tert-butyl hydroperoxide (t-BHP)-induced RAW264.7 macrophages [21]. In tert-BHP- and tacrine-challenged HepG2cell, fucosterol treatment caused a reduction in ROS and thereby attenuated oxidative stress by increasing glutathione level [22]. Fucosterol from Sargassum binderi protected against oxidative stress in particulate matter-induced injury and inflammation model of A549 human lung epithelial cells by accumulating SOD, CAT, and HO-1 in the cytosol, and Nrf2 levels in the nucleus [23]. A steroidal antioxidant, 7-dehydroerectasteroid F, isolated from the soft coral Dendronephthya gigantea was shown to protect against H₂O₂-induced oxidative damage in PC12 cells by enhancing nuclear translocation of Nrf2 and subsequent activation of HO-1 expression [16]. These protective effects of marine sterols against oxidative injury suggest their potential efficacy against oxidative stress-associated neurological disorders, including AD (Figure 1).

In microglia challenged with extrinsic and intrinsic toxic stimuli, there is an elevated expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), and secretion of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), which can stimulate neurons to cause degeneration, ultimately leading to AD. Natural products, including phytosterols that attenuate inflammatory signals can be beneficial in the management of AD [53,54,55]. Mounting evidence suggests anti-inflammatory potentials of marine sterols. Fucosterol treatment of lipopolysaccharide (LPS)- or Aβ-stimulated microglial cells ameliorated inflammation by lowering the secretion of IL-1β, IL-6, TNF-α, nitric oxide (NO), and PGE2 [24]. Fucosterol attenuated the inflammatory response in LPS-stimulated RAW 264.7 macrophages by downregulating COX-2 and iNOS expression and suppressing NF-κB signaling [21]. Fucosterol can also attenuate LPS-mediated inflammation by suppressing NF-κB activation and stimulating alveolar macrophages [56]. In CoCl₂-challenged cells, fucosterol inhibited inflammatory response by lowering the production of TNF-α, IL-6, and IL-1β [26]. Fucosterol attenuated particulate matter-induced inflammation by inhibiting activation and nuclear translocation of NF-κB and phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and COX-2 [23]. Fucosterol of Undaria pinnatifida downregulated the transcription of iNOS, TNF-α, and IL-6, and inhibited their production. Moreover, fucosterol inhibited LPS-mediated activation and nuclear translocation of NF-κB. In addition, fucosterol attenuated activation of mitogen-activated protein kinase kinases 3/6 (MKK3/6) and MAPK-activated protein kinase 2 (MK2) of the MAPK pathway, suggesting that the anti-inflammatory effects of fucosterol may be, at least in part, associated with the inactivation of NF-κB and p38 MAPK pathways [25].

Apart from algal sterols, there are some other marine sterols that are also important as anti-inflammatory agents. Two steroids, 5α-pregn-20-en-3β-ol and 5α-cholestan-3,6-dione, isolated from an octocoral Dendronephthya mucronate, were shown to inhibit LPS-induced NO production in activated RAW264.7 murine macrophage cells [18]. Another octocoral sterol, dendronesterones D, isolated from Dendronephthya sp., inhibited the expression of iNOS and COX-2, and thereby protected against inflammation [17]. Anti-inflammatory effects of marine sterols suggest their potential in protecting against neuroinflammation in AD pathology (Figure 2).

The cholinergic deficit has been established as a clinical consequence of AD pathology. Cholinesterase inhibitors that can temporarily slow down cholinergic neurotransmission can improve AD outcomes. Marine sterols have also been shown to inhibit the activity of cholinesterase. Fucosterol and 24-hydroperoxy 24-vinylcholesterol showed inhibition against butyrylcholinesterase (BChE) with IC₅₀ values of 421.72 ± 1.43 and 176.46 ± 2.51 μM, respectively [27]. In another study, fucosterol exhibited dose-dependent inhibition against acetylcholinesterase (AChE) and BChE activities [24]. Enzyme kinetics and structural analysis demonstrated that fucosterol acts as a non-competitive inhibitor to AChE [47].

The aggregation of Aβ represents a characteristic hallmark of AD. β-secretase, which catalyzes the initial breakdown of amyloid precursor protein (APP) to generate Aβ, may represent a promising target for the development of an anti-AD agent [57]. However, evidence suggests that complete inhibition of β-secretase activity might have unintended sequelae with behavioral deficits [58]. Natural products that bear reversible and non-competitive binding patterns with β-secretase may therefore bear therapeutic promise against AD. Natural products, including marine sterols, possess anti-amyloidogenic potential. Fucosterol can be such a potential candidate due to its anti-β-secretase activity [48]. The mode of inhibition is of noncompetitive type, indicating that fucosterol could be an effective and safer inhibitor. Additionally, as shown in computational analysis, fucosterol can be docked on the active site of β-secretase via hydrogen bonding and hydrophobic interactions [59]. Moreover, fucosterol shows competitive binding energies of −10.1 [48] and −19.88 kcal/mol [59], respectively, indicating that hydrogen bonding may ensure close association with enzyme active site, leading to a more effective β-secretase inhibition. Moreover, hecogenin and cholest-4-en-3-one isolated from fat innkeeper worm Urechis unicinctus exhibited anti-β-secretase activity with EC50 of 390.6 µM and 116.3 µM, respectively [29]. With this evidence, these marine sterols can be a potent anti-amyloidogenic agent for use against AD (Figure 3).

Aβ aggregation initiates neuroinflammation and thereby can contribute to the pathobiology of AD. Marine sterols have been shown to protect against Aβ-induced cytotoxicity and clear Aβ in several studies. Fucosterol protected against Aβ_1–42 (sAβ_1–42)-mediated cytotoxicity and suppressed glucose-regulated protein 78 (GRP78) expression in cultured hippocampal neurons by upregulating tropomyosin receptor kinase B (TrkB)-mediated ERK1/2 signaling [49] (Figure 4). These in vitro effects of fucosterol were further translated into an in vivo model, in which fucosterol co-treatment ameliorated sAβ_1–42-induced cognitive impairment in aging rats through suppression of GRP78 expression and upregulation of BDNF expression in the dentate gyrus [49]. In Aβ-induced SH-SY5Y cells, fucosterol pretreatment attenuated neurotoxicity by upregulating neuroglobin (Ngb) mRNA expression [50]. Fucosterol preconditioning also decreased APP mRNA and lowered Aβ levels in activated SH-SY5Y cells [50]. Supplementation of astrocytes with 24(S)-saringosterol caused an increase in ApoE secretion. Furthermore, supplementation of microglia with conditioned medium of 24(S)-saringosterol-treated astrocytes augmented microglial clearance of Aβ_1–42. 24(S)-saringosterol reduces Aβ₄₂ release in APP overexpressing neuronal N2a cells [30]. 16-O-desmethylasporyergosterol-β-d-mannoside isolated from marine-derived fungus Dichotomomyces cejpii exhibited a moderate Aβ-42 lowering activity in APP-overexpressing aftin-5-treated N2a cells [28]. 4-methylenecholestane-3β,5α,6β,19-tetraol attenuated glutamate-induced neuronal injury, prevented N-methyl-D-aspartate (NMDA)-induced intracellular calcium increase, and inhibited NMDA currents, suggesting that this marine-derived sterol could also have therapeutic potential against glutamate excitotoxicity [51].

Cholesterol is known to regulate cell-to-cell communication and transmembrane signaling [60], and is critical in the development and maintenance of central nervous system (CNS) neurons. A defect in cholesterol metabolism results in synaptic dysfunction, oxidative stress and inflammation, triggering the onset of AD pathology [61]. Activation of LXR-β upregulates several genes of reverse cholesterol transport, including apolipoprotein E (ApoE), ATP-binding cassette transporter (ABCA1), ATP binding cassette subfamily G member 1 (ABCG1), and sterol regulatory element-binding protein 1 (SREBP1), and thereby this nuclear receptor plays a significant role in the protection against neurodegeneration [42,43]. Upon ligand activation, LXR-β attenuated dopaminergic loss [62] and reduced the toxic burden of mutant huntingtin [63], and also accelerated Aβ clearance [44]. Experimentally, acting as a selective LXR-β agonist, fucosterol augmented the expression of LXR target genes encoding ABCA1, ABCG1, and ApoE [31,52]. This evidence demonstrates that fucosterol may produce similar LXR-β-mediated effects to aid in brain cholesterol homeostasis and play a pivotal role against AD pathology involving Aβ clearance via ABC/SHREBP1/ApoE-dependent pathways (Figure 3). Saringasterol is also a selective LXRβ agonist and promoted the transcriptional activation of ABCA1, ABCG1, and SREBP-1c in multiple cell lines and thus is suggested to be a potent natural cholesterol-lowering agent [31].