Marine-Derived Compounds with Anti-Alzheimer’s Disease Activities

Alzheimer’s disease (AD) is an irreversible and progressive brain disorder that slowly destroys memory and thinking skills, and, eventually, the ability to perform simple tasks. As the aging population continues to increase exponentially, AD has become a big concern for society. Therefore, neuroprotective compounds are in the spotlight, as a means to tackle this problem. On the other hand, since it is believed—in many cultures—that marine organisms in an individual diet cannot only improve brain functioning, but also slow down its dysfunction, many researchers have focused on identifying neuroprotective compounds from marine resources. The fact that the marine environment is a rich source of structurally unique and biologically and pharmacologically active compounds, with unprecedented mechanisms of action, marine macroorganisms, such as tunicates, corals, sponges, algae, as well as microorganisms, such as marine-derived bacteria, actinomycetes, and fungi, have been the target sources of these compounds. Therefore, this literature review summarizes and categorizes various classes of marine-derived compounds that are able to inhibit key enzymes involved in AD, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase (BACE-1), and different kinases, together with the related pathways involved in the pathogenesis of AD. The compounds discussed herein are emerging as promising anti-AD activities for further in-depth in vitro and in vivo investigations, to gain more insight of their mechanisms of action and for the development of potential anti-AD drug leads.


Introduction
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder affecting more than 50 million people across the world [1]. Although the pathogenesis of the disorder is complicated, it is directly related to the central nervous system (CNS) and generally emerges by a slow and irreversible progression of dementia, which is terminated with not only a decrease in cognition and memory, but also an alteration of languages, thinking, calculation, and personal behaviors [2]. The understanding of AD causality is still incomplete and a serious debate regarding whether AD is a singularly distinct form of dementia is ongoing [3]. Besides genetic and environmental factors [4,5], to date, several factors, including cholinesterase (acetyl-and butyrylcholinesterase) enzymes [6], proteases with β-site amyloid precursor protein cleaving cascade (β-and γ-secretases) [7], β-amyloid (Aβ) aggregation [3,8], protein kinase C [9], tau protein [3,10], glycogen-synthase kinase 3β (GSK-3β) [11], neurodegenerators [12], and oxidants [13] are recognized in this brain dysfunction. Moreover, metals, especially zinc, also have a key role in neuronal signaling and neurotransmission. However, whether this metal dyshomeostasis or aggregation in the brain is associated with AD is yet to be unraveled [14]. Given that AD is an age-related
The n-BuOH fraction of the extract of a marine sponge Petrosia n. sp., collected in the intertidal zone of Phuket Island in Thailand, furnished petrosamine (35) and 2-bromoamphimedine (36) (Figure 3). Structural analysis revealed that 35 could exist in both keto (35a) and enol (35b) forms; however, the latter was detected only when D 2 O and CD 3 OD were used for NMR solvents. The AChE inhibitory activity assay, using AChE from the electric eel Torpedo californica (TcAChE), revealed that 35 exhibited potent AChE inhibitory activity (IC 50 = 0.091 µM), which is about six times the potency of the reference compound galantamine (IC 50 = 0.590 µM), whereas 36 showed only very weak potency, with IC 50 value > 300 µM. ADocking study using two different crystal structures viz. 1DX6-and 1EVE-proteins of TcAChE, which are TcAChEs complexed with galantamine and donepezil, respectively, revealed that the calculated binding free energies for both systems of 35a is approximately the same as those of 35b, which are less than those of galantamine, whereas the free energies of 36 were the highest. The docking study results are in good agreement with their experimental IC 50 values. Moreover, it also revealed direct interactions between galantamine, 35a, 35b and the two catalytic residues, Ser-200 and His-440, whereas 36 lacks an interaction with these two residues. Moreover, the docking data indicated that the quaternary dimethyl ammonium group in ring D of 35 donates major and strong interactions to the key amino acid residues located in the binding site (Glu-199 and Ser-200) of the enzyme [36]. The secondary metabolites from the marine sponges Latrunculia biformis and L. bocagei, obtained from coastal shelf environments around the Antarctic Peninsula, were also investigated for their anti-AChE activity. While the methanol extract of L. biformis furnished (+)-discorhabdins G (37) and (-)-3-dihydro-7,8dehydrodiscorhabdin C (38), the methanol extract of L. bocagei gave (+)-discorhabdins B (39) and L (40) (Figure 3), all belonging to the discorhabdin subclass, which is structurally Mar. Drugs 2021, 19, 410 6 of 34 characterized by an additional sulfur bridge between C-5 and C-8. These alkaloids were assayed for their inhibitory activities against eeAChE, recombinant hAChE and eqBuChE. All compounds tested effectively inhibited the activities of cholinesterases in a dose-dependent manner, with the highest activity against eeAChE. Moreover, 37 and 39 were found to be the most potent AChE inhibitors of the series, with IC 50 values of 1.3 µM and 5.7 µM towards eeAChE, and 116 µM and 49.5 µM towards hAChE, respectively (physostigmine was used as a positive control with IC 50 = 3 µM towards eeAChE, and 14.5 µM towards hAChE). The Ki values of 35 and 37 were 1.6 µM and 1.9 µM towards eeAChE, and 56.2 µM and 22.8 µM towards hAChE, respectively. On the other hand, 37 (IC 50 = 7 µM) and 38 (IC 50 = 15.8 µM) showed the strongest inhibition against eqBuChE among the tested compounds (IC 50 of the reference compound, physostigmine salicylate, was 28.5 µM). Moreover, the kinetic of the inhibition of these cholinesterases by the tested compound, together with their analysis using Dixon plots, revealed that 37 and 39 act as reversible and competitive inhibitors through their binding to the active site of the free AChE or BuChE. The docking results for TcAChE showed that 37 had the lowest value of energies and the highest number of hydrophobic interactions, although with no specific hydrogen bonds, which is in agreement with the highest inhibitory activity observed. Moreover, the docking results for each of the tested compounds with hAChE showed higher energy and fewer hydrophobic interactions when compared with the inhibition of TcAChE. For the complex of 37 with hAChE, the computational data showed lower stability, fewer hydrophobic interactions and lack of hydrogen bonds when compared to the complex of 37 with TcAChE, thus supporting the experimental results that 37 had higher inhibitory activity against TcAChE than hAChE [37].
4-Acetoxyplakinamine B (41) (Figure 3), a stigmastane-type steroidal alkaloid, was isolated from the methanol extract of a marine sponge Corticium sp., collected in Southern Thailand. Compound 41 moderately inhibited eeAChE activity (IC 50 = 3.75 µM) compared to the positive control, galantamine (IC 50 = 0.59 µM). Kinetic study revealed an unusual mixed-competitive mode of inhibition of 41 [38]. The docking study indicated a strong potential for 41 to penetrate in and bind with the active subsites of AChE binding pocket. Simultaneous and favorable bonding interactions of 41 with PAS and anionic subsites (AS) provided a major clue behind its significant AChE inhibitory activity and mixedcompetitive kinetic profile [39].
Sepcic et al. isolated polymeric pyridinium compounds (poly-APS), which are composed of two polymers of 29 and 99 repeating N-butyl(3-butylpyridinium) units (42) (Figure 3), from a marine sponge Reniera sarai, collected in the Northern Adriatic Sea. Poly-APS exhibited strong anti-AChE activity with an unusual pattern of inhibition, suggesting several mechanisms were involved. In order to have more insight of their AChE inhibitory activity and mechanisms, its monomeric unit, N-butyl-3-butylpyridinium iodide (42), was synthesized and evaluated for its anti-AChE activity. Kinetic study suggested that both polymeric and monomeric compounds inhibited AChE activity by irreversible and mixed-reversible patterns [40].
posed of two polymers of 29 and 99 repeating N-butyl (3-butylpyridinium) units (42) (Figure 3), from a marine sponge Reniera sarai, collected in the Northern Adriatic Sea. Poly-APS exhibited strong anti-AChE activity with an unusual pattern of inhibition, suggesting several mechanisms were involved. In order to have more insight of their AChE inhibitory activity and mechanisms, its monomeric unit, N-butyl-3-butylpyridinium iodide (42), was synthesized and evaluated for its anti-AChE activity. Kinetic study suggested that both polymeric and monomeric compounds inhibited AChE activity by irreversible and mixedreversible patterns [40].  Yang et al. isolated nine depsidone derivatives, along with a cyclic peptide, from the EtOAc extract of cultures of a seaweed-associated fungus Aspergillus unguis DLEP2008001, collected from the South China Sea, and from the plasma-induced mutant of this fungus. Among the isolated depsidones, only aspergillusidone A (48) (Figure 4), isolated from the plasma-induced mutant, showed AChE inhibition with IC50 value of 56.8 μM (donepezil, a positive control, IC50 = 0.3 μM). In order to get an insight of the different anti-AChE activities between 48 and a structurally related analog, aspergillusidone G (49, IC50 > 102.4 μM), molecular docking studies were performed. Docking results showed that the docked pose of 48 with AChE has a negative CDOCKER energy of 7.86 kcal/mol and a negative CDOCKER interaction energy of 46.07 kcal/mol. Compound 48 also formed two hydrogen bonds between its 4-OH and Trp-84 (4.7 Å) as well as between its 10-COOH and Tyr-121 (6.5 Å). Moreover, electrostatic (Tyr-121, Trp-84, etc.) and van der Waals (Tyr-334, Phe-331, Phe-330, Ser-122, etc.) interactions also exist between 48 and AChE. All these interactions are known to be formed between potent AChE inhibitors and the enzyme active site. On the contrary, the docked pose of 49 with AChE has a negative CDOCKER energy of 10.02 kcal/mol and a negative CDOCKER interaction energy of 44.43 kcal/mol. Compound  Yang et al. isolated nine depsidone derivatives, along with a cyclic peptide, from the EtOAc extract of cultures of a seaweed-associated fungus Aspergillus unguis DLEP2008001, collected from the South China Sea, and from the plasma-induced mutant of this fungus. Among the isolated depsidones, only aspergillusidone A (48) (Figure 4), isolated from the plasma-induced mutant, showed AChE inhibition with IC 50 value of 56.8 µM (donepezil, a positive control, IC 50 = 0.3 µM). In order to get an insight of the different anti-AChE activities between 48 and a structurally related analog, aspergillusidone G (49, IC 50 > 102.4 µM), molecular docking studies were performed. Docking results showed that the docked pose of 48 with AChE has a negative CDOCKER energy of 7.86 kcal/mol and a negative CDOCKER interaction energy of 46.07 kcal/mol. Compound 48 also formed two hydrogen bonds between its 4-OH and Trp-84 (4.7 Å) as well as between its 10-COOH and Tyr-121 (6.5 Å). Moreover, electrostatic (Tyr-121, Trp-84, etc.) and van der Waals (Tyr-334, Phe-331, Phe-330, Ser-122, etc.) interactions also exist between 48 and AChE. All these interactions are known to be formed between potent AChE inhibitors and the enzyme active site. On the contrary, the docked pose of 49 with AChE has a negative CDOCKER energy of 10.02 kcal/mol and a negative CDOCKER interaction energy of 44.43 kcal/mol. Compound 49 mainly formed one hydrogen bond with AChE, i.e., between 4-OH and Tyr-70 (bond length 5.1 Å). However, electrostatic (Tyr-121, Ser-122, Trp-84, etc.) and van der Waals (Trp-84, Tyr-334, Phe-331, Phe-330, etc.) interactions exist between 49 and AChE [42]. The extracts of a culture broth and mycelia of a marine sponge-associate fungus Talaromyces sp. strain LF458, isolated from tissues of a marine sponge Axinella verrucosa, which was collected at Punta di Fetovaia, Isle of Elba (Mediterranean Sea) Italy, furnished, among other compounds, the anti-AChE metabolites viz. oxaphenalenone dimer, talaromycesone A (50), a penicillide derivative, AS-186c (51), and an isopentenyl xanthenone, talaroxanthenone (52) (Figure 4). Compound 52 showed the highest inhibitory activity toward AChE with IC 50 value of 1.61 µM, followed by 51 with IC 50 value of 2.63 µM, and 50 with IC 50 value of 7.49 µM. The positive control, huperzine A, showed IC 50 = 11.6 µM [43]. The methanol extract of a fermentation broth of a deep sea-derived fungus Ochroconis sp. FS449, isolated from a sediment collected from the Indian Ocean, yielded highly oxygenated usnic acid derivatives, ochuscins A-G (53-59) (Figure 4). Compounds 53-59 were evaluated for their anti-AChE activity by Ellman's method, however, 54-56 and 59 exhibited moderate anti-AChE activity, with IC 50 values ranging from 50 to 75 µM (a positive control neostigmine displayed IC 50 value of 0.99 µM) whereas 53, 57, and 58 were inactive (IC 50 > 200 µM) [44].

Phenolics
A dimeric polybrominated benzofuran, iantheran A (60) (Figure 5), isolated from a marine sponge Ianthella sp., which was collected from the Great Barrier Reef, Australia, inhibited the AChE activity with an IC 50 value of 0.42 µM [45].
AChE and competitive inhibitors of BuChE, with Ki values of 0.58, 0.71, and 0.64 μM for AChE inhibition, and 1.15, 0.51, and 0.37 μM for BuChE inhibition, respectively. A docking study, using tacrine and donepezil as models, elucidates the binding mode of 65-67 in the active gorge of the Tetronarce californica AChE enzyme (1acj). Docking data showed that 65-67 were involved in the interaction with His-440 of CAS, in particular, 65 and 67 showed the hydrogen bond interaction with His-440 whereas 66 interacted with His-440 through the Br-O bond. Moreover, 65-67 also bound to PAS through interactions involving Tyr-334, Asp-72, Trp-84, and Tyr-121. In addition, 67 displayed more interactions with respect to the number of bromine atoms when compared to 65 and 66. Thus, 65-67 showed mixed-type inhibition mode, binding to both CAS and PAS of AChE, with binding energies −7.47, −7.37, and −10.9 kcal/mol, respectively. In relation to BuChE, docking study showed catalytic inhibition of BuChE with low binding energies (−6.17, −6.44, and −9.80 kcal/mol, respectively). Compound 65 was involved in hydrogen bond interaction with Pro-285 and halogen bond interactions with His-438 (π−π T-shaped), Trp-231, Leu-286, Phe-329, and Gly-116. On the contrary, 66 displayed four hydrogen bond interactions with His-438, Ser-198, and Pro-285 (two hydrogen bonds), together with nonpolar interactions with Trp-231, Ala-199, Val-288, Leu-286, and Phe-329. On the other hand, 67, which had the lowest binding energy among the three compounds and the reference compound, displayed multiple bond interactions with His-438 (two hydrogen bonds and one nonpolar interaction) and Trp-82 (three hydrogen bonds and one nonpolar interaction). Moreover, 67 also showed nonpolar interactions with Ala-328, Trp-430, Phe-329, and Gly-116. Taking together, 65-67 displayed competitive mode of BuChE inhibition through interactions with residues of CAS [48].

Sesquiterpenes
Li et al. isolated a polychiral bisabolane sesquiterpene, bisabolanoic acid A (68) (Figure 6), from a culture of a mangrove-associated fungus Colletotrichum sp. SCSIO KcB3-2, obtained from a mangrove plant K. candel, collected in Guangdong Province, China. Compound 68 showed a moderate inhibition of AChE activity with IC50 value of 2.2 μM (IC50 value of a positive control, huperzine A, is 0.30 μM). A docking study, using several crystal structures of AChE, showed that 68 was able to bind to the active pocket of different crystal structures of AChE, with Tyr-121 as the center of the binding site of AChE. Using the crystal structure 5EI5 of AChE, it was shown that the hydroxyl groups at C-7 and C-   (Figure 6), from a culture of a mangrove-associated fungus Colletotrichum sp. SCSIO KcB3-2, obtained from a mangrove plant K. candel, collected in Guangdong Province, China. Compound 68 showed a moderate inhibition of AChE activity with IC 50 value of 2.2 µM (IC 50 value of a positive control, huperzine A, is 0.30 µM). A docking study, using several crystal structures of AChE, showed that 68 was able to bind to the active pocket of different crystal structures of AChE, with Tyr-121 as the center of the binding site of AChE. Using the crystal structure 5EI5 of AChE, it was shown that the hydroxyl groups at C-7 and C-11 formed hydrogen bond interactions with the active site residue Tyr-121 and Ser1-22 of AChE while the carboxylic acid group also interacted with Arg-289 and Phe-288 by hydrogen bond. Consequently, it was deduced that OH-7, OH-11, and COOH-15 of 68 could play a key role for the inhibitory activity [49].
Onchidal (69) (Figure 6), a sesquiterpene containing an α/β-unsaturated aldehyde and an acetate group, was isolated from the mucous secretion of the mollusk Onchidella binneyi. Compound 69 inhibited AChE in a progressive and apparently irreversible manner. The apparent affinity of 69 for the initial reversible binding to AChE (Kd) was approximately 300 µM [50]. Stoddard et al., in their docking study of 69, have found that 69 interacts with the esteratic site of AChE, which is consistent with Abramson's work [50]. In the three poses generated for 69, the cyclohexane ring is positioned in the bottleneck between the surface of AChE and the active site residues. In two of the three poses, the acetate ester is in the oxyanion hole. The lowest energy pose for 69 was generated from the 1DX6 receptor and places the acetate ester in the oxyanion hole, the aldehyde in the acyl pocket and the cyclohexane ring of 69 in the bottleneck created by Phe-330 and Tyr-121. The major interactions were potential hydrogen bond interactions with Gly-118 and Gly-119 of the oxyanion hole, hydrophobic contacts with the bottleneck and a possible hydrogen bond with His-440 of the catalytic triad. The irreversible inhibition of AChE by 69 makes it unsuitable for a direct use as an AChE inhibitor for human diseases since permanent inhibition of AChE leads to potentially deadly cholinergic toxicity. However, 69 could have a potential application in insecticides or pesticides. The interaction of 69 with the oxyanion hole is a new mechanistic area for incorporation into rational drug design of novel inhibitors [51].
With the aid of chemogenomics techniques, five halogenated sesquiterpenes viz. (−)elatol (70), (+)-elatol (71), (+)-obtusol (72), (−)-dendroidol (73), and (−)-cartilagineol (74) (Figure 6), isolated from different populations of a red alga Laurencia dendroidea, collected off the coast of Brazil, were evaluated for their AChE inhibitory activity. Compounds 71 and 72 did not exhibit significant activities whereas 70, 73, and 74 were able to inhibit the enzyme with percent inhibition of 78.5%, 72.9%, and 61.3% respectively. Kinetic study of 70 confirmed its noncompetitive type of inhibition with Ki value of 255.9 µM. Molecular docking of 70 showed its interactions with important specific residues of the enzyme gorge involved in the activity of drugs used for treatment of AD. In particular, interactions between bromine and chlorine atoms with the center of the benzene ring of Tryp-86 and Tryp-286 may be contributing to the observed activity [52].

Diterpenes
Anti-AChE activity-guided fractionation of the crude extract of a coral Pseudoplexaura porosa led to the isolation of 14-acetoxycrassine (75) ( Figure 6). Anti-AChE activity assay by Ellman's method of 75 and asperdiol (76) ( Figure 6), a cembrane diterpene previously isolated from the sea whip Eunicea knighti, collected from the Colombian Caribbean [53] showed that both compounds exhibited a dose-dependent inhibition of AChE with IC 50 values of 1.40 µM and 0.358 µM, respectively, which are less active than the positive control, galantamine (IC 50 = 0.118 µM) [54].
Syad et al., in a continuation of their work on a red alga Gelidiella acerosa [55], have used a bioassay-guided fractionation of the benzene extract by column chromatography. The fractions showing anti-AChE and anti-BuChE activities were pooled and analyzed for its chemical constituents by LC-MS. Among several compounds detected, phytol (77) ( Figure 6) was found to be a major component. Since 77 has been reported to have bioprotective potential, a pure phytol (77) was assayed for its anti-AChE and anti-BuChE activities. Compound 77 inhibited AChE and BuChE activities with IC 50 values of 95.27 and 2.07 µg/mL, respectively. The molecular docking study showed that 77, like the control ligands (rivastigmine, donepezil, galantamine) binds to Arg-277 at the active site of AChE [56].
The petroleum ether fraction of the crude aqueous ethanol extract of a marine sponge Xestospongia testudinaria, collected from the coast of Sanya ( (Figure 6), isolated from the extract of a sea weed Sargassum horridum. Compared with the positive control, neostigmine, kinetic study showed that 87 is a noncompetitive hAChE inhibitor and has higher affinity than neostigmine for hAChE. Molecular docking results showed that both 87 and neostigmine are coupled to the AChE binding site, sharing a similar map of contacts. Most of the residues that stabilize the two complexes are hydrophobic residues with free energy values in picomolar and nanomolar range for 87 (−10.68 kcal/mol) and neostigmine (−7.02 kcal/ mol), respectively, suggesting that 87 not only has a higher affinity for AChE than neostigmine, but also acts as a noncompetitive hAChE inhibitor, which is different from a stabilization of galantamine (competitive hAChE inhibitor) [59].
Castro-Silva et al. evaluated the in vitro and in silico AChE inhibitory activity of fucosterol (87) (Figure 6), isolated from the extract of a sea weed Sargassum horridum. Compared with the positive control, neostigmine, kinetic study showed that 87 is a noncompetitive hAChE inhibitor and has higher affinity than neostigmine for hAChE. Molecular docking results showed that both 87 and neostigmine are coupled to the AChE binding site, sharing a similar map of contacts. Most of the residues that stabilize the two complexes are hydrophobic residues with free energy values in picomolar and nanomolar range for 87 (−10.68 kcal/mol) and neostigmine (−7.02 kcal/ mol), respectively, suggesting that 87 not only has a higher affinity for AChE than neostigmine, but also acts as a noncompetitive hAChE inhibitor, which is different from a stabilization of galantamine (competitive hAChE inhibitor) [59].

Tetraterpenes
Fucoxanthin (88) (Figure 7) is a natural carotenoid which is abundant in edible brown seaweeds and possesses a myriad of biological activities [60]. Lin et al. isolated 88 from S. horneri to evaluate its effects on cognitive impairment in vivo and its capacity to inhibit some key enzymes in vitro. Compound 88, at 100 and 200 mg/kg, and donepezil significantly reduced the scopolamine-induced increase of AChE activity in the hippocampus of ICR mice. In an in vitro AChE activity assay, 88 was shown to directly inhibit AChE activity with an IC 50 value of 81.2 µM. Moreover, kinetic study showed that 88 is a noncompetitive inhibitor of AChE, with Ki value of 42 µM for AChE. Molecular docking study reveals that 88 showed favorable interaction mainly with PAS of AChE by forming hydrogen bonds with Asp-283 and Ser-286 residues [61].

Meroterpenoids
Asperpenes D (89) and E (90) (Figure 7) were obtained from the EtOAc extract of a marine-derived fungus Aspergillus sp. SCS-KFD66, isolated from a bivalve mollusk Sanguinolaria chinensis, which was collected from Haikou Bay, China. Compound 90, at a concentration of 50 µg/mL, exhibited weak inhibitory activity against AChE, with an inhibition rate of 19.5% (the positive control, tacrine has an IC 50 = 0.02 µM) [62]. Territrem B (91) (Figure 7), obtained from the extract of a liquid culture of a marine-derived fungus A. terreus BCC51799, isolated from a decayed wood sample from the Gulf of Thailand, exhibited anti-AChE activity with IC 50 = 0.071 µM (IC 50 of galantamine, a positive control = 0.097 µM) [63]. Nong et al. described the isolation of eight territrem derivatives and nine butyrolactone derivatives form the EtOAc extract of a solid culture of a marine-derived fungus A. terreus SCSGAF0162, isolated from a gorgonian coral Echinogorgia aurantiaca, which was collected in the South China Sea. The isolated compounds were assayed for their anti-AChE activity by Ellman's method, however, only 91, territrems C (92), D (93), and E (94), arisugacin (95), and terreulactone C (96) (
The petroleum ether fraction of the crude extract of a marine sponge Xestospongia testudinaria furnished unsaturated fatty acids and their esters viz. xestospongic acid (104)

Miscellaneous Compounds
Among four brominated aliphatic hydrocarbons, isolated from a crude extract of a marine sponge X. testudinaria, mutafuran H (113) (Figure 8) showed significant in vitro inhibition of AChE enzyme with IC 50 = 0.64 mM [58].
A glycoprotein with a molecular weight of approximately 10 kDa, consisting of carbohydrate (42.53%) and protein components (57.47%), was isolated from an edible brown macroalgae Undaria pinnatifida Harvey, purchased from the market in Korea [70]. This glycoprotein inhibited AChE and BuChE activities with IC50 values of 63.56 and 99.03 μM, respectively [71].

Marine-Derived Compounds That Inhibit β-Secretase (BACE-1) and γ-Secretase Activities
The β-amyloid (Aβ) peptide is widely considered to play a critical role in the pathogenesis of AD. Aggregates of Aβ are generated by cleavage of the amyloid precursor protein (APP) by β-secretase (BACE-1), followed by γ-secretase. BACE-1 cleavage is limiting for the production of Aβ, making it a particularly good drug target for inhibitors that lower the amount of soluble Aβ, preventing and/or reversing their aggregation. Interestingly, some marine-derived compounds have been proved to inhibit BACE-1 and, thus, preventing Aβ aggregation [72].

Marine-Derived Compounds That Inhibit β-Secretase (BACE-1) and γ-Secretase Activities
The β-amyloid (Aβ) peptide is widely considered to play a critical role in the pathogenesis of AD. Aggregates of Aβ are generated by cleavage of the amyloid precursor protein (APP) by β-secretase (BACE-1), followed by γ-secretase. BACE-1 cleavage is limiting for the production of Aβ, making it a particularly good drug target for inhibitors that lower the amount of soluble Aβ, preventing and/or reversing their aggregation. Interestingly, some marine-derived compounds have been proved to inhibit BACE-1 and, thus, preventing Aβ aggregation [72].
Ianthellidone F (118), a pyrrolidone alkaloid, and lamellarins O (119), O1 (120), and O2 (121) (Figure 9), were isolated from the extract of a marine sponge Ianthella sp. CMB-01245, which was collected in Southern Australia. Compounds 118, 119, and 121 moderately inhibited BACE-1 activity with an IC50 value > 10 μM (40% inhibition at a concentration of 10 μM) whereas 120 showed a stronger activity (IC50 < 10 μM; 60% inhibition at a concentration of 10 μM). Although their levels of BACE-1 inhibition are modest, the ianthellidones and lamellarins can be considered as potential scaffolds for a development of BACE-1 inhibitor [76]. The same research group has further explored the extract of the same sponge and has isolated five dictyodendrins, i.e., dictyodendrins F (122), G (123), H (124), I (125), and J (126) (Figure 9), a rare class of marine alkaloids belonging to the lamellarin and ianthellidone structural classes. Compounds 122, 124-126 exhibited significant BACE-1 inhibitory activity, with IC50 values ranging from 1 to 2 μM whereas 123 was inactive. Interestingly, 122-125 exhibited cytotoxicity against human colon cancer cell line SW620, being 123, the 10-OMe analog, the most cytotoxic. On the other hand, 126 that possesses a seco-carbon skeleton and an unusual 1,2-diketone functionality did not exhibit cytotoxicity, which is worth further investigation [77].   (Figure 10), recovered from a marine sponge A. verrucosa, which was collected in the Gulf of Naples, were found to inhibit the murine BACE-1 with IC 50 values of 0.9 and 1.4 µM, respectively. Molecular docking and MD studies showed that both 140 and 141 possibly bind to both "open" and "closed" states of hBACE-1 active site [30].

Phenolics
Compound 64 ( Figure 5), isolated form the alga G. elliptica, inhibited BACE-1 activity with 18.6% inhibition at a concentration of 1 μM (the standard reference, Z-Val-Leu-Leu-CHO, showed 75% inhibition at 1 μM) [47], while 66 and 67, isolated from the red alga S. latiuscula (Harvey) Yamada, also exhibited significant inhibition of BACE-1 activity with IC50 values of 5.16, 4.79, and 2.32 μM, respectively. Interestingly, the BACE-1 inhibition potential of the three compounds was 5-10-fold higher than the reference drug, quercetin (IC50 = 25.21 μM). In order to better understand the inhibitory mechanism of BACE-1, the interactions of 65-67 with the BACE-1 structure were evaluated by molecular docking simulation. The results showed that 65 and 67 bound to the active allosteric site of BACE-1 with low energies (−6.59 and −5.98 kcal/mol, respectively). However, these interacting residues are not involved in the binding of 67 to the enzyme. The determining factors for competitive inhibition by 67 were the interactions with the catalytic Asp dyad (Asp-32−Asp-228), Ser-36, Ile-126, and Gly-230), which were not observed for 65 and 66 [48].
The chlorinated phenolic metabolites, saccharochlorines A (142) and B (143) ( Figure  11), isolated from the saline culture of a marine-derived bacterium Saccharomonospora sp. KCTC-19160, exhibited weak inhibition of BACE-1 activity (42.4% and 32.0% inhibition, respectively) at a concentration of 50 μM (a positive control, isoliquiritigenin showed 56.7% inhibition at 50 μM). Moreover, treatment of both compounds did not cause any increase in levels of Aβ40 and Aβ42 in the SH-SY5Y neuroblastoma cells. On the contrary, both compounds caused an increase in Aβ40 and Aβ42 levels in a dose-dependent manner in H4-APP neuroglial cells, therefore exhibiting a stimulatory effect on the release of Aβ40 and Aβ42 in H4-APP cells. The authors suggested that the contradiction between the biochemical BACE-1 inhibitory assay and the cell-based BACE-1 inhibitory assay might be due to a difference in the efficiency of BACE-1 in cleaving APP, which depends on cellular

Phenolics
Compound 64 ( Figure 5), isolated form the alga G. elliptica, inhibited BACE-1 activity with 18.6% inhibition at a concentration of 1 µM (the standard reference, Z-Val-Leu-Leu-CHO, showed 75% inhibition at 1 µM) [47], while 66 and 67, isolated from the red alga S. latiuscula (Harvey) Yamada, also exhibited significant inhibition of BACE-1 activity with IC 50 values of 5.16, 4.79, and 2.32 µM, respectively. Interestingly, the BACE-1 inhibition potential of the three compounds was 5-10-fold higher than the reference drug, quercetin (IC 50 = 25.21 µM). In order to better understand the inhibitory mechanism of BACE-1, the interactions of 65-67 with the BACE-1 structure were evaluated by molecular docking simulation. The results showed that 65 and 67 bound to the active allosteric site of BACE-1 with low energies (−6.59 and −5.98 kcal/mol, respectively). However, these interacting residues are not involved in the binding of 67 to the enzyme. The determining factors for competitive inhibition by 67 were the interactions with the catalytic Asp dyad (Asp-32−Asp-228), Ser-36, Ile-126, and Gly-230), which were not observed for 65 and 66 [48].
The chlorinated phenolic metabolites, saccharochlorines A (142) and B (143) (Figure 11), isolated from the saline culture of a marine-derived bacterium Saccharomonospora sp. KCTC-19160, exhibited weak inhibition of BACE-1 activity (42.4% and 32.0% inhibition, respectively) at a concentration of 50 µM (a positive control, isoliquiritigenin showed 56.7% inhibition at 50 µM). Moreover, treatment of both compounds did not cause any increase in levels of Aβ 40 and Aβ 42 in the SH-SY5Y neuroblastoma cells. On the contrary, both compounds caused an increase in Aβ 40 and Aβ 42 levels in a dose-dependent manner in H4-APP neuroglial cells, therefore exhibiting a stimulatory effect on the release of Aβ 40 and Aβ 42 in H4-APP cells. The authors suggested that the contradiction between the biochemical BACE-1 inhibitory assay and the cell-based BACE-1 inhibitory assay might be due to a difference in the efficiency of BACE-1 in cleaving APP, which depends on cellular models and subcellular environments. This was supported by the fact that isoliquiritigenin, a BACE-1 inhibitor, elevated Aβ secretion in H4-APP culture media and C-terminal fragment-β (CTF-β) concentration in the cells, respectively [79].
Williams's group described the isolation of two pentacyclic diketones, named xestosaprols D (144) and E (145) (Figure 11), from the extract of a marine sponge Xestospongia sp., collected from the Indonesian waters. Compound 144 showed weak inhibition of BACE-1 activity with IC 50 value of 30 µg/mL [80]. The same research group has further explored the chemistry of the marine sponge Xestospongia sp., collected at the coral reef from the Indonesian waters. The EtOAc-soluble fraction of its crude extract furnished eight xestosaprol analogs, named xestosaprols F-M (146-153) ( Figure 11). Compounds 146-153 exhibited a moderate dosedependent inhibition of BACE-1 with IC 50 values ranging from 82 to 163 µM (IC 50 of the positive control, the secretase inhibitor IV = 0.015 µM) [81].
Fucofuroeckol-b (154) (Figure 11), an eckol derivative, was obtained by bioassayguided isolation from the EtOAc fraction of the crude ethanol extract of a brown alga Eisenia bicyclis, collected from the coast of South Korea. Compound 154 showed a strong β-secretase inhibition with IC 50 value of 16.1 µM. Kinetic study revealed a noncompetitive inhibition pattern of 154 in the Dixon plot, with Ki value of 10.1. Compound 154 was also attenuated Aβ-induced cytotoxicity in SH-SY5Y cells, probably by inhibition of β-secretase-mediated downregulation of Aβ. Moreover, the western blot results indicated that treatment with 154 decreased soluble-APPβ (sAPPβ) and Aβ 42 expression in a dosedependent manner in SH-SY5Y cells overexpressing APP695swe (SH-SY5Y-APP695swe cells) [82]. explored the chemistry of the marine sponge Xestospongia sp., collected at the coral reef from the Indonesian waters. The EtOAc-soluble fraction of its crude extract furnished eight xestosaprol analogs, named xestosaprols F-M (146-153) ( Figure 11). Compounds 146-153 exhibited a moderate dose-dependent inhibition of BACE-1 with IC50 values ranging from 82 to 163 μM (IC50 of the positive control, the secretase inhibitor IV = 0.015 μM) [81].
Fucofuroeckol-b (154) (Figure 11), an eckol derivative, was obtained by bioassayguided isolation from the EtOAc fraction of the crude ethanol extract of a brown alga Eisenia bicyclis, collected from the coast of South Korea. Compound 154 showed a strong βsecretase inhibition with IC50 value of 16.1 μM. Kinetic study revealed a noncompetitive inhibition pattern of 154 in the Dixon plot, with Ki value of 10.1. Compound 154 was also attenuated Aβ-induced cytotoxicity in SH-SY5Y cells, probably by inhibition of β-secretase-mediated downregulation of Aβ. Moreover, the western blot results indicated that treatment with 154 decreased soluble-APPβ (sAPPβ) and Aβ42 expression in a dose-dependent manner in SH-SY5Y cells overexpressing APP695swe (SH-SY5Y-APP695swe cells) [82].

Diterpenoids
In the course of investigation of the effects of gracilin diterpenoids, isolated from a marine sponge Spongionella sp., for their capacity to intervene with processes involved in the pathology of AD, Leiros et al. have evaluated the in vitro capacity to inhibit the enzyme β-secretase of gracilins A (157), H (158), L (159), and tetrahydroaplysulphurin-1 (160) (Figure 12) by using a Free Resonance Energy Transfer (FRET) assay kit. The results showed that only 159 at 1 mM was able to produce a significant inhibition of BACE-1, decreasing its activity by 24.6%. Although 157 and 160 also reduced BACE-1 activity at 1

Diterpenoids
In the course of investigation of the effects of gracilin diterpenoids, isolated from a marine sponge Spongionella sp., for their capacity to intervene with processes involved in the pathology of AD, Leiros et al. have evaluated the in vitro capacity to inhibit the enzyme β-secretase of gracilins A (157), H (158), L (159), and tetrahydroaplysulphurin-1 (160) (Figure 12) by using a Free Resonance Energy Transfer (FRET) assay kit. The results showed that only 159 at 1 mM was able to produce a significant inhibition of BACE-1, decreasing its activity by 24.6%. Although 157 and 160 also reduced BACE-1 activity at 1 mM, their inhibition was not in a significant manner. Treating retinoic acid differentiated neuroblastoma BE(2)-M17 cells with 157-160, at concentrations of 1 and 0.1 mM for 24 h, did not have any effect on Aβ 42 levels. In addition, the levels of Aβ 42 , hyperphosphorylated tau, and extracellular signal-regulated kinase (ERK) at Ser-202 and Thr-205 were reduced after treatments with gracilins in vitro [84] Ki values of 4.0 and 1.6 mM, respectively, whereas 101 exhibited a noncompetitive inhibition with Ki value of 2.9 mM. Molecular docking study revealed that the three compounds not only formed a number of strong hydrogen bonds with several important amino acid residues located in the catalytic and allosteric sites of BACE-1, but also possessed a num-ber of hydrophobic interactions with BACE-1, thus explaining their potency against this enzyme [67].
Lopez-Ogalla et al. used prenylated hydroxybenzoic acid (161) (Figure 12), isolated from a marine sponges Spongia officinalis, Ircinia spinulosa, I. muscarum, collected at different locations in the Mediterranean Sea, as a scaffold to design BACE-1 inhibitor. They have found that both natural and synthetic 161 inhibited Aβ 1-40 production in a micromolar range. The percent inhibition of natural 161 was found to be 10% at 1 µM and 47% at 10 µM. Further studies on its mechanism of action showed that natural 161 also inhibited BACE-1 activity with a percent inhibition of 45% at 1 µM. Interestingly, the synthetic version showed slightly lower inhibitory activities for both Aβ formation and BACE-1 [85].

Peptides
Tasiamide B (164) (Figure 13), a linear depsipeptide containing eight amino acid residues, was isolated from a marine cyanobacterium Symploca sp. [88]. Liu et al. [89] noticed that the presence of a statin-like unit (4-amino-3-hydroxy-5-phenylpentanoic acid, AHPPA) in the structure of 164 might have an affinity to the active site of BACE-1. Compound 164 and modified peptides with a central statin-core unit, which are characteristic of aspartic protease inhibitors, were synthesized and evaluated for BACE-1 inhibitory ac-

Peptides
Tasiamide B (164) (Figure 13), a linear depsipeptide containing eight amino acid residues, was isolated from a marine cyanobacterium Symploca sp. [88]. Liu et al. [89] noticed that the presence of a statin-like unit (4-amino-3-hydroxy-5-phenylpentanoic acid, AHPPA) in the structure of 164 might have an affinity to the active site of BACE-1. Compound 164 and modified peptides with a central statin-core unit, which are characteristic of aspartic protease inhibitors, were synthesized and evaluated for BACE-1 inhibitory activity. The synthetic 164 exhibited inhibition of BACE-1 with IC 50 = 353 nM (IC 50 of the positive control, β-secretase inhibitor IV = 250 nM). By measuring secreted amounts of Aβ peptides formed upon sequential action of βand γ-secretases in CHO 2B7 cells (clonal expression of APP695 wt), it was found that the activity of 164 was in a micromolar range, and thus exhibiting potency approximately 10-100-fold lower than in the enzymatic BACE-1 assay [89]. Tasiamide F (165) (Figure 13), an analog of 164, was isolated together with 164 from the EtOAc fraction of the crude extract of a marine cyanobacterium Lyngbya sp., collected from patch reefs in Cocos Lagoon, Guam. Compound 165 inhibited BACE-1 activity (IC 50 = 690 nM), which is approximately 8-fold less potent than 164 (IC 50 = 80 nM) [90].
Lee et al. isolated β-secretase inhibitory peptide, with IC 50 = 24.26 µM, from an enzymatic hydrolysate by neutrase enzyme of a skate (Raja kenojei) skin, obtained from a local skate processing plant in Korea. The amino acid sequence of this peptide was identified by MS/MS as Gln-Gly-Thr-Arg-Pro-Leu-Arg-Gly-Pro-Glu-Phe-Leu (166) (Figure 13), with a molecular weight of 1391 Da [91]. In another study, Lee et al. have used various enzymes to hydrolyze the muscle of sea hare (Aplysia kurodai) and have found that the trypsin hydrolysate had the highest β-secretase inhibitory activity compared to other hydrolysates. Purification of the hydrolysate by Sephadex G-25 column chromatography and HPLC using a C18 column, followed by amino acid sequence analysis by MS/MS revealed the structure of the active peptide as Ala-Ala-Leu-Met-Leu-Phe-Asn (167) (Figure 13). The peptide 167 exhibited IC 50 = 74.25 µM, and acts as a competitive inhibitor against β-secretase [92]. A peptide with amino acid sequence Ser-Leu-Ala-Phe-Val-Asp-Asp-Val-Leu-Asn (168) (Figure 13), purified from a protein hydrolysate of Pacific hake (Merluccius productus) by Sephadex G-25 column chromatography and ODS-C18 reversed-phase HPLC, exhibited potent β-secretase inhibitory activity (IC 50 = 18.65 µM) in SH-SY5Y cells stably transfected with the human "Swedish" amyloid precursor protein (APP) mutation APP695 (SH-SY5YAPP695swe) [93].
Among the hydrolysates obtained from hydrolysis of blackfin flounder (Glyptocephalus stelleri) muscle protein with various commercial proteases, the Alcalase hydrolysate exhibited the highest β-secretase inhibitory activity compared with other hydrolysates. Purification of this hydrolysate by Sephadex G-25 column chromatography and reversed-phase HPLC using an ODS column, followed by amino acid sequence analysis by electrospray ionization MS/MS led to the characterization of an inhibitor as a pentapeptide Leu-Thr-Gln-Asp-Trp (169) (Figure 13) with a molecular mass of 526.7 Da. This peptide showed an IC 50 = 126.93 µM [94].

Polycyclic Ethers
Alonso et al. examined the effect of Gambierol (170), a polycyclic ether toxin produced by a dinoflagellate Gambierdiscus toxicus, and its synthetic heptacyclic (171) and tetracyclic (172) analogues ( Figure 13) in an in vitro model of AD, obtained from triple transgenic (3xTg-AD) mice that express Aβ accumulation and tau hyperphosphorylation. They have found that 170-172 decreased both intra-and extracellular Aβ levels and tau hyperphosphorylation via modulation of N-methyl-D-aspartate (NMDA) receptors that is possibly secondary to voltage-gated potassium (K v ) channel inhibition in an in vitro mouse model of AD [95]. Furthermore, both 170 and 172 displayed a dose-dependent inhibition of BACE-1 activity, falling to 52.25% with 170 and to 58.04% with 172, at 10 µM [96]. racyclic (172) analogues ( Figure 13) in an in vitro model of AD, obtained from triple transgenic (3xTg-AD) mice that express Aβ accumulation and tau hyperphosphorylation. They have found that 170-172 decreased both intra-and extracellular Aβ levels and tau hyperphosphorylation via modulation of N-methyl-D-aspartate (NMDA) receptors that is possibly secondary to voltage-gated potassium (Kv) channel inhibition in an in vitro mouse model of AD [95]. Furthermore, both 170 and 172 displayed a dose-dependent inhibition of BACE-1 activity, falling to 52.25% with 170 and to 58.04% with 172, at 10 μM [96].

Marine-Derived Compounds That Inhibit Aβ Aggregation
Overexpression of BACE-1 is a key factor for an increase of Aβ peptides generation as well as BACE-1-cleaved APP fragments. In addition, it results in an imbalance between Aβ production and clearance, leading to aggregate formation. Since the effect of Aβ aggregation is neurotoxic and, consequently, related to neuroinflammation and neuronal dysfunction in AD patients, finding effective drugs that are capable of preventing Aβ aggregation is of great interest [97]. A number of marine-derived compounds, belonging to different chemical classes, have been shown to inhibit or decrease Aβ aggregation.

Marine-Derived Compounds That Inhibit Aβ Aggregation
Overexpression of BACE-1 is a key factor for an increase of Aβ peptides generation as well as BACE-1-cleaved APP fragments. In addition, it results in an imbalance between Aβ production and clearance, leading to aggregate formation. Since the effect of Aβ aggregation is neurotoxic and, consequently, related to neuroinflammation and neuronal dysfunction in AD patients, finding effective drugs that are capable of preventing Aβ aggregation is of great interest [97]. A number of marine-derived compounds, belonging to different chemical classes, have been shown to inhibit or decrease Aβ aggregation.
Liu et al. examined a neuroprotective effect of the bis-indole alkaloids, racemosins A (173) and B (174), and caulerpin (175) (Figure 14), obtained from the EtOAc fraction of the crude aqueous ethanol extract of a green alga Caulerpa racemose, which was collected from the Zhanjiang coastline in the East China Sea, by using Aβ 25-35 -induced neurotoxicity in SH-SY5Y cells assay-guided isolation. Compound 173 exhibited neuroprotection with 14.6% increase in cell viability at a concentration of 10 µM, whereas 174 and 175 showed weak to moderate neuroprotective activity with 5.5% and 8.1% increase in cell viability at a concentration of 10 µM, respectively. The positive control, epigallocatechin gallate (EGCG), showed 16.57% increase in cell viability at 10 µM [98].
(173) and B (174), and caulerpin (175) (Figure 14), obtained from the EtOAc fraction of the crude aqueous ethanol extract of a green alga Caulerpa racemose, which was collected from the Zhanjiang coastline in the East China Sea, by using Aβ25-35-induced neurotoxicity in SH-SY5Y cells assay-guided isolation. Compound 173 exhibited neuroprotection with 14.6% increase in cell viability at a concentration of 10 μM, whereas 174 and 175 showed weak to moderate neuroprotective activity with 5.5% and 8.1% increase in cell viability at a concentration of 10 μM, respectively. The positive control, epigallocatechin gallate (EGCG), showed 16.57% increase in cell viability at 10 μM [98].

Phenolics
Xanthocillin X dimethyl ether (176) (Figure 15) was obtained from the culture of a marine sponge-associated fungus Dichotomomyces cejpii, isolated from a sample of a marine sponge Callyspongia sp. cf. C. flammea, which was collected at Bare Island, Sydney, Australia. Compound 176 was evaluated for its capacity to decrease a production of Aβ42 in N2a cells, stably transfected with human APP695 (N2a-APP695 cells) induced by aftin-5. It was found that cells solely treated with 100 μM aftin-5 displayed a fold change (the amount of Aβ peptides produced by treated cells compared with the Aβ peptides produced by untreated cells) of ±9.4, whereas a pretreatment with 10 μM of 176 reduced the fold of change to ±2.9. A positive control N-[N- (3,5-

Phenolics
Xanthocillin X dimethyl ether (176) (Figure 15) was obtained from the culture of a marine sponge-associated fungus Dichotomomyces cejpii, isolated from a sample of a marine sponge Callyspongia sp. cf. C. flammea, which was collected at Bare Island, Sydney, Australia. Compound 176 was evaluated for its capacity to decrease a production of Aβ 42 in N2a cells, stably transfected with human APP695 (N2a-APP695 cells) induced by aftin-5. It was found that cells solely treated with 100 µM aftin-5 displayed a fold change (the amount of Aβ peptides produced by treated cells compared with the Aβ peptides produced by untreated cells) of ±9.4, whereas a pretreatment with 10 µM of 176 reduced the fold of change to ±2.9. A positive control N-[N-(3,5-difluorophenylacetyl)-L-alanyl-]-(S)-phenylglycine-tbutylester (DAPT), a known inhibitor of Aβ 42 production, reduced the fold change to ±0.3 [99].

Meroterpenoids
An α-tocopherol derivative, α-tocospirone (180) (Figure 16), isolated from the EtOAcsoluble fraction of the crude aqueous ethanol extract of a green alga Caulerpa racemosa, collected from the Zhanjiang coastline in the East China Sea, displayed a significant effect against Aβ25-35-induced cell damage in SH-SY5Y cells with 13.6% increase in cell viability at 10 μM [101].

Meroterpenoids
An α-tocopherol derivative, α-tocospirone (180) (Figure 16), isolated from the EtOAcsoluble fraction of the crude aqueous ethanol extract of a green alga Caulerpa racemosa, collected from the Zhanjiang coastline in the East China Sea, displayed a significant effect against Aβ 25-35 -induced cell damage in SH-SY5Y cells with 13.6% increase in cell viability at 10 µM [101].

Meroterpenoids
An α-tocopherol derivative, α-tocospirone (180) (Figure 16), isolated from the EtOAcsoluble fraction of the crude aqueous ethanol extract of a green alga Caulerpa racemosa, collected from the Zhanjiang coastline in the East China Sea, displayed a significant effect against Aβ25-35-induced cell damage in SH-SY5Y cells with 13.6% increase in cell viability at 10 μM [101].

Tetraterpenes
Compound 88 (Figure 7), extracted from a seaweed S. horneri, was found to inhibit Aβ1-42 fibrils formation by ThT assay. Interestingly, 88 exhibited a greater potency of inhibition of the formation of Aβ1-42 fibrils when compared with curcumin, an inhibitor of Aβ fibrils formation. Compound 88, at 0.1-1 μM, substantially reduced the formation of Aβ1- 42 oligomers in a dot blotting assay. Moreover, small amounts of irregular aggregates were observed in the sample after coincubation of 88 and Aβ1-42, suggesting that 88 largely altered the shape of Aβ1-42 assemblies. Moreover, the cell viability of SH-SY5Y cells decreased to ca. 50% by treatment with 1 μM of 88-modified Aβ1−42 oligomers, suggesting that 88-modified Aβ1−42 oligomers were less toxic than Aβ1−42 oligomers to SH-SY5Y cells. Analysis of direct interactions between 88 and Aβ1−42 peptide, based on the trajectories of all-atom MD simulations, reveals that nine molecules of 88 clustered with each other,

Tetraterpenes
Compound 88 (Figure 7), extracted from a seaweed S. horneri, was found to inhibit Aβ 1-42 fibrils formation by ThT assay. Interestingly, 88 exhibited a greater potency of inhibition of the formation of Aβ 1-42 fibrils when compared with curcumin, an inhibitor of Aβ fibrils formation. Compound 88, at 0.1-1 µM, substantially reduced the formation of Aβ 1-42 oligomers in a dot blotting assay. Moreover, small amounts of irregular aggregates were observed in the sample after coincubation of 88 and Aβ 1-42 , suggesting that 88 largely altered the shape of Aβ 1-42 assemblies. Moreover, the cell viability of SH-SY5Y cells decreased to ca. 50% by treatment with 1 µM of 88-modified Aβ 1−42 oligomers, suggesting that 88-modified Aβ 1−42 oligomers were less toxic than Aβ 1−42 oligomers to SH-SY5Y cells. Analysis of direct interactions between 88 and Aβ 1−42 peptide, based on the trajectories of all-atom MD simulations, reveals that nine molecules of 88 clustered with each other, bound to Aβ 1−42 peptide, and formed stable aggregates, which could inhibit the conformational transition of Aβ 1−42 and a subsequent aggregation. Moreover, analysis of the atomic contacts between molecules of 88 and Aβ 1−42 monomers indicated that 88 directly bound to Aβ 1−42 peptide mainly via hydrophobic interactions [102].

Miscellaneous
Homotaurine (3-amino-1-propanesulfonic acid) (6) (Figure 1) is a naturally occurring metabolite of various marine red algae [106,107]. Compound 6 has been considered as a potential treatment for AD as it binds to soluble Aβ and decreases Aβ 42 -nduced cell death in neuronal cell culture [108].

Marine-Derived Compounds That Inhibit Protein Kinases
Inhibition of either protein kinase Cθ (PKCθ) or protein kinase Cδ (PKCδ) could effectively reduce Aβ levels and reverse AD phenotypes [109]. In addition, targeting the serine/threonine protein kinase, glycogen synthase kinase 3β (GSK-3β), is an important clue in several signaling pathways, such as cell proliferation, apoptosis, inflammation, and glycogen metabolism, which are involved in treatment of AD, Parkinson's disease and type 2 diabetes mellitus [110]. The most significant approach that has been recently pursued is multitarget-directed ligands (MTDLs), including the GSK-3β enzyme. Indeed, protein kinases and phosphatases control tau phosphorylation, and any imbalance between them caused the tau phosphorylation and consequently aggregation [111]. Several classes of marine-derived compounds are found to be PKC inhibitors.

Alkaloids
Biscogniauxone (184) (Figure 17), an isopyrrolonaphthoquinone obtained from the methanol extract of the culture of a marine-derived fungus Biscogniauxia mediterranea strain LF657, isolated from a sediment collected in the Eastern Mediterranean Sea (2800 m depth), was found to inhibit GSK-3β, with an IC 50  Compounds 192-194 are predicted for their preference to bind in the ATP binding pocket. However, the hydroxyl and steric methoxy groups were pointing in the opposite direction to the hinge region (Cys-83) and few hydrogen bonds were formed with the protein backbone [112].
protein kinases and phosphatases control tau phosphorylation, and any imbalance between them caused the tau phosphorylation and consequently aggregation [111]. Several classes of marine-derived compounds are found to be PKC inhibitors.

Alkaloids
Biscogniauxone (184) (Figure 17), an isopyrrolonaphthoquinone obtained from the methanol extract of the culture of a marine-derived fungus Biscogniauxia mediterranea strain LF657, isolated from a sediment collected in the Eastern Mediterranean Sea (2800 m depth), was found to inhibit GSK-3β, with an IC50 value of 8.04 μM. The positive control, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) showed an IC50 value of 0.26 μM [69]. Plisson et al., in their screening program of a collection of approximately 2600 Southern Australian and Antarctic marine invertebrates and algae, for the ability to inhibit CK1d, CDK5, and GSK-3β, combined with chemical (HPLC-DAD-MS) and spectroscopic ( 1 H NMR) profiling of the extracts that inhibited these protein kinases, have identified an ascidian Didemnum sp. (CMB-02127), collected off the Northern Rottnest Shelf, Western Australia, as a high potential extract. This extract furnished several members of pyrrolepolyphenol alkaloids, including ningalins A-G (185-191) and lamellarins Z (192), G (193), and A6 (194) (Figure 17) . Compounds 186-191, and to a lesser extent, 192-194 Compounds 192-194 are predicted for their preference to bind in the ATP binding pocket. However, the hydroxyl and steric methoxy groups were pointing in the opposite direction to the hinge region (Cys-83) and few hydrogen bonds were formed with the protein backbone [112].  Hymenialdisine (195) (Figure 18) was first isolated in 1982 from the marine sponges Axinella verrucosa and Acanthella aurantiaca [113]. Further investigation showed that 195 is a cyclin-dependent kinases inhibitor, especially toward GSK-3β and CK1 (IC 50 = 10 and 35 nM, respectively). Compound 195 also blocked the phosphorylation of tau protein at sites that are hyperphosphorylated by GSK-3β and CDK5/p35 in AD. Moreover, the inhibitory activity of 195 was examined against CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, CDK3/cyclin E, and CDK5/p35, in the presence of 15 µM ATP, presenting IC 50 (Figure 18) are able to inhibit the special kinases, i.e., CDK1/cyclin B, CDK5/p35, GSK-3β, and CK1, which were moderately sensitive to 196, with IC 50 values ranging from 3 to 7 µM. On the other hand, 197 and 198 selectively inhibited GSK-3β and CDK5/p35, with IC 50 values of 3 and 4 µM, respectively [114]. Plisson et al. have isolated several bromopyrrole alkaloids, including from the extract of a marine sponge Callyspongia sp. (CMB-01152) which displayed inhibitory activity against the neurodegenerative disease kinase targets: CK1, CDK5, and GSK-3β. However, the kinase inhibitory activity detected in the sponge extract was found to be due to 195, a major metabolite whose IC 50 values against kinases were 0.03 µM for CK1δ, 0.16 µM for cyclin-dependent kinase (CDK5/p25), and 0.07 µM for GSK-3β [115]. Leucettamine B (199) (Figure 18) is a marine-derived imidazole alkaloid, first isolated from a sponge Leucetta microraphis Haechel, collected from Argulpelu Reef in Palau at a depth of 30 m [116]. Debdabe et al. synthesized 199 and its derivatives (leucettines) and assayed them on eight purified kinases, including tyrosine phosphorylation regulated kinases (DYRK1A and DYRK2), cdc2-like kinases (CLK1 and CLK3), CDK5/p25, CK1, GSK-3β, and Pim1. Compound 199 inhibited DYRK1A, DYRK2, CLK1, and CLK3, with IC 50 values of 2.8, 1.5, 0.40, and 6.4 µM, respectively, but did not show any inhibitory activity (IC 50 [117]. Furthermore, Tahtouh et al., in their study to compare the activity of 199 and 200 with harmine (a reference DYRK1A inhibitor) against a panel of 26 kinases to confirm the potential therapeutics of leucettines against neurodegenerative diseases such as AD, have found that 200 was a potential kinases inhibitor. Interestingly, 200 not only showed a neuroprotective potency on glutamate-induced HT22 cell death, but also reduced the APP-induced cell death in cultured rat brain slices [118].

Terpenoids
Sesquiterpenes Palinurin (218) ( Figure 20) is a linear furanosesquiterpene, isolated from a Mediterranean sponge Ircinia dendroides. Both naturally occurring and synthetic version of 218 were found to dose-dependently inhibit GSK-3β in human neuroblastoma cells SH-SY5Y, with IC50 values of 2.6 mM and 1.9 mM, respectively. Kinetic study revealed its noncompetitive inhibition. Moreover, GSK-3β inhibition by 218 can be competed neither by ATP nor peptide substrate, therefore strongly suggesting that the binding site for 218 lays outside the binding pockets for both ATP and the substrate. A docking study and MD simulations suggested that 218 exerts its inhibitory activity through binding to an allosteric site located at the N-terminal lobe of the enzyme. Binding of 218 to this unconventional site modulates the accessibility of ATP γ-phosphate by constraining the conformation of the glycine-rich loop. The authors proposed that this novel allosteric mechanism of action confers 218 a high degree of selectivity towards GSK-3β with respect to other kinases, making it an interesting candidate molecule for the development of new selective and

Terpenoids Sesquiterpenes
Palinurin (218) (Figure 20) is a linear furanosesquiterpene, isolated from a Mediterranean sponge Ircinia dendroides. Both naturally occurring and synthetic version of 218 were found to dose-dependently inhibit GSK-3β in human neuroblastoma cells SH-SY5Y, with IC 50 values of 2.6 mM and 1.9 mM, respectively. Kinetic study revealed its noncompetitive inhibition. Moreover, GSK-3β inhibition by 218 can be competed neither by ATP nor peptide substrate, therefore strongly suggesting that the binding site for 218 lays outside the binding pockets for both ATP and the substrate. A docking study and MD simulations suggested that 218 exerts its inhibitory activity through binding to an allosteric site located at the N-terminal lobe of the enzyme. Binding of 218 to this unconventional site modulates the accessibility of ATP γ-phosphate by constraining the conformation of the glycine-rich loop. The authors proposed that this novel allosteric mechanism of action confers 218 a high degree of selectivity towards GSK-3β with respect to other kinases, making it an interesting candidate molecule for the development of new selective and more potent drug for the treatment of GSK-3β-mediated diseases [125].

Miscellaneous Marine Natural Products
The culture filtrate of a fermentation of a marine member of Streptomyces griseus 16S rRNA clade, strain NTK 935, which was isolated from a deep-sea sediment collected from the Canary Basin, furnished 1,4-benzoxazine-type metabolite, named benzoxacystol (223) (Figure 20). Compound 223 showed an in vitro inhibitory activity against GSK-3β with IC 50 value of 1.35 µM [127].

Marine-Derived Compounds with Miscellaneous Enzyme Inhibition
An anabaseine-like derivative, 3-[(2,4-dimethoxy]benzylidene]-anabaseine (GTS-21; 117), isolated from a nemertean (ribbon worm, Amphiporus sp.), has been reported to exhibit an agonist activity on α7 nicotinic acetylcholine receptors. In addition to suppression of the γ-secretase activity in vitro and in vivo, 117 was found to not only promote microglial Aβ phagocytosis in APdE9 mice but also ameliorate cognitive impairment in a mouse model of AD [75] In recent years, great effort has been made to unravel new enzymes and pathways, which are involved in AD. One group of these enzymes is glutaminyl cyclases (QCs),

Marine-Derived Compounds with Miscellaneous Enzyme Inhibition
An anabaseine-like derivative, 3-[(2,4-dimethoxy]benzylidene]-anabaseine (GTS-21; 117), isolated from a nemertean (ribbon worm, Amphiporus sp.), has been reported to exhibit an agonist activity on α7 nicotinic acetylcholine receptors. In addition to suppression of the γ-secretase activity in vitro and in vivo, 117 was found to not only promote microglial Aβ phagocytosis in APdE9 mice but also ameliorate cognitive impairment in a mouse model of AD [75] In recent years, great effort has been made to unravel new enzymes and pathways, which are involved in AD. One group of these enzymes is glutaminyl cyclases (QCs), which belong to the class of acyl transferases. QCs could be associated with pathophysiological processes of various diseases including AD [129]. Evidences revealed that QCs are responsible for the formation of pGlu-modified Aβ peptides in AD, which are more neurotoxic, hydrophobic, and resistant to aminopeptidase degradation compared to unmodified Aβ peptides and, thus, accumulating in AD patients' brains [130] Therefore, inhibition of QCs may have therapeutic potential for treatment of disorders associated with protein aggregation and (neuro) inflammation and, therefore, might be considered as one of therapeutic approaches in treatment of AD [131].  (230), isolated form a microalga Scenedesmus sp. by using a new reverse metabolomics approach. Compounds 228-230 displayed QCs inhibition ranging from 76% to 81% at concentrations of 0.025 and 0.25 mg/mL, respectively [132].
It is important to mention also that during a protein glycation process, a kind of compounds, named advanced glycation end products (AGEs), are generated. Accumulation of AGEs is found in the brain of the aging and AD patients [133]. For this reason, the potency of a seaweed Fucus vesiculosus fractions and its purified phlorotannins were investigated for their capacity to prevent protein glycation using two methods viz. Bovine Serum Albumin (BSA)-methylglyoxal and BSA-glucose assays. In both assays, the EtOAc fraction showed a promising activity with EC 50 value of 0.169 and 0.278 mg/mL, respectively. Further purification of the active fraction led to the isolation of fucophlorethol (231), tetrafucol (232), and trifucodiphlorethol (233) (Figure 21) [134]. of AGEs is found in the brain of the aging and AD patients [133]. For this reason, the potency of a seaweed Fucus vesiculosus fractions and its purified phlorotannins were investigated for their capacity to prevent protein glycation using two methods viz. Bovine Serum Albumin (BSA)-methylglyoxal and BSA-glucose assays. In both assays, the EtOAc fraction showed a promising activity with EC50 value of 0.169 and 0.278 mg/mL, respectively. Further purification of the active fraction led to the isolation of fucophlorethol (231), tetrafucol (232), and trifucodiphlorethol (233) (Figure 21) [134].

Future Perspectives and Conclusions
This review highlights the importance of marine organisms as a new source of compounds with promising anti-AD activities. The search for new sources of marine-derived compounds with a capacity to cure or prevent neurodegenerative diseases is very crucial, as a number of patients suffering from these diseases is rapidly increasing due to the aging population, especially in highly developed countries. Overall, we have listed 233 marinederived compounds that possess biological and pharmacological activities, which are considered to be relevant for therapeutic targets for AD. Among the compounds discussed, 102 exhibited anti-AChE and anti-BuChE activities, 68 showed anti-BACE-1 activity, 17 showed anti-Aβ aggregation, 44 inhibited protein kinases activities, and 7 are inhibitors of other enzymes related to AD. Although a significant number of inhibitors of enzymes implicated in AD pathogenesis has been discovered during the past decade, a broader range of therapeutics is still needed. Given the diverse pathology of AD, targeting only the key enzymes could not be the most effective way to treat AD. Interestingly, the most significant approach that has been recently pursued is multitarget-directed ligands (MTDLs), targeting the GSK-3β enzyme with multiple mechanisms. This goal can be achieved by marine natural products due to their structural uniqueness and their unprecedented mechanisms of actions, which are not found in synthetic and terrestrial natural

Future Perspectives and Conclusions
This review highlights the importance of marine organisms as a new source of compounds with promising anti-AD activities. The search for new sources of marine-derived compounds with a capacity to cure or prevent neurodegenerative diseases is very crucial, as a number of patients suffering from these diseases is rapidly increasing due to the aging population, especially in highly developed countries. Overall, we have listed 233 marine-derived compounds that possess biological and pharmacological activities, which are considered to be relevant for therapeutic targets for AD. Among the compounds discussed, 102 exhibited anti-AChE and anti-BuChE activities, 68 showed anti-BACE-1 activity, 17 showed anti-Aβ aggregation, 44 inhibited protein kinases activities, and 7 are inhibitors of other enzymes related to AD. Although a significant number of inhibitors of enzymes implicated in AD pathogenesis has been discovered during the past decade, a broader range of therapeutics is still needed. Given the diverse pathology of AD, targeting only the key enzymes could not be the most effective way to treat AD. Interestingly, the most significant approach that has been recently pursued is multitarget-directed ligands (MT-DLs), targeting the GSK-3β enzyme with multiple mechanisms. This goal can be achieved by marine natural products due to their structural uniqueness and their unprecedented mechanisms of actions, which are not found in synthetic and terrestrial natural products. In summary, marine-derived compounds can be potential candidates for the development of therapeutic arsenals for AD, per se, or can be explored as unique and unprecedented scaffolds for medicinal chemistry research to discover potent and effective therapeutics for AD. Funding: This work was funded by the structured program of R&D&I ATLANTIDA-Platform for the monitoring of the North Atlantic Ocean and tools for the sustainable exploitation of the marine re-sources (reference NORTE-01-0145-FEDER-000040), supported by the North Portugal Regional Operational Program (NORTE2020), through the European Regional Development Fund (ERDF) and also by national funds through FCT-Foundation for Science and Technology with the scope of UIDB/04423/2020 and UIDP/04423/2020.