Exploitation of Marine Molecules to Manage Alzheimer’s Disease

marine drugs Review Exploitation of Marine Molecules to Manage Alzheimer’s Disease Marisa Silva 1,2 , Paula Seijas 3and Paz Otero 3,4,5,*   Citation: Silva, M.; Seijas, P.; Otero, P. Exploitation of Marine Molecules to Manage Alzheimer’s Disease. Mar. Drugs 2021,19, 373. https://doi.org/ 10.3390/md19070373 Academic Editor: Bill J. Baker Received: 2 June 2021 Accepted: 23 June 2021 Published: 28 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1MARE—Marine and Environmental Sciences Centre, Faculty of Sciences, University of Lisbon, Campo Grande, 1749-016 Lisbon, Portugal; [email protected] 2Department of Plant Biology, Faculty of Science, University of Lisbon, Campo Grande, 1749-016 Lisbon, Portugal 3Department of Pharmacology, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; [email protected] 4Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence UAM+CSIC, 28049 Madrid, Spain 5Nutrition and Bromatology Group, CITACA, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, 32004 Ourense, Spain *Correspondence: [email protected] or paz.oter[email protected] Abstract: Neurodegenerative diseases are sociosanitary challenges of today, as a result of increased average life expectancy, with Alzheimer’s disease being one of the most prevalent. This pathology is characterized by brain impairment linked to a neurodegenerative process culminating in cognitive decline and behavioral disorders. Though the etiology of this pathology is still unknown, it is usually associated with the appearance of senile plaques and neurofibrillary tangles. The most used prophylaxis relies on anticholinesterase drugs and NMDA receptor antagonists, whose main action is to relieve symptoms and not to treat or prevent the disease. Currently, the scientific community is gathering efforts to disclose new natural compounds effective against Alzheimer’s disease and other neurodegenerative pathologies. Marine natural products have been shown to be promising candidates, and some have been proven to exert a high neuroprotection effect, constituting a large reservoir of potential drugs and nutraceutical agents. The present article attempts to describe the processes of extraction and isolation of bioactive compounds derived from sponges, algae, marine bacteria, invertebrates, crustaceans, and tunicates as drug candidates against AD, with a focus on the success of pharmacological activity in the process of finding new and effective drug compounds. Keywords: Alzheimer’s disease; marine drugs; sponges; algae; yields; natural products 1. Introduction Neurodegenerative diseases (NDs) are the XXI century paradigm, since they result from progressive loss of structure and/or function of neurons, sometimes leading to cell death [ 1 ]. One of the dominant factors for the escalation of these pathologies is the increase in the average life expectancy. Aging stands as a common factor to a diverse group of syndromes, and still few therapeutic advances towards finding a cure have been achieved. NDs represent the seventh leading cause of mortality worldwide, and their prevalence increases exponentially with age [ 2 ]. One of the most common NDs is Alzheimer’s disease (AD), which was first diagnosed and described by the German neurologist Dr. Alois Alzheimer in 1906 and is the most common cause of dementia in the elderly [ 3 ]. The term dementia is defined as a chronic progressive mental disorder that affects memory, thinking, understanding, and other essential brain functions [ 4 ]. This is characterized by a progressive loss of neurons, which results in brain atrophy mainly in the memory and learning areas of the brain. Consequently, motor, sensory, emotional, and cognitive alterations emerge [ 5 ]. Currently, there are approximately 50 million people who suffer from dementia worldwide, and this number is expected to increase to 66 million by 2030 and to 115 million by 2050 [6]. Mar. Drugs 2021,19, 373. https://doi.org/10.3390/md19070373 https://www.mdpi.com/journal/marinedrugs Mar. Drugs 2021,19, 373 2 of 26 Alzheimer’s is characterized by the presence of amyloid-beta plaques and neurofibrillary tangles that are formed in the patient’s brain, and its pathogenesis is multifactorial. The origin of the disease is associated with the mutations in three major genes encoding amyloid precursor protein (APP) on chromosome 21, presenilin-1 (PS1) on chromosome 14, and presenilin-2 (PS2) [ 7 ]. The mutations in these genes lead to the formation of senile plaques in the extracellular region by amyloidβ protein (A β ) and the hyperphosphorylation of tau protein that forms the neurofibrillary tangles intracellularly [ 8 ]. This causes widespread damage to nerve cells throughout the brain cortex, accompanied by early loss of cholinergic neurons from the basal region of the forebrain. The duration of AD is approximately from 8 to 10 years. In most cases, the patients who have been diagnosed with this disease are over 65 years old. The cause of AD occurrence is unknown; however, several hypotheses try to explain the development of this pathology [ 7 ]. The most important theories are described below. The first hypothesis is the amyloid cascade. According to this hypothesis, the accumulation of amyloid-beta (amyloid plaques) triggers a cascade of events that lead to synaptic dysfunction, memory loss, and structural damage in the brain in the advanced stages of the disease [ 9 ]. Another theory is the cholinergic hypothesis, which is based on the significant loss of cholinergic signaling. This occurs due to a severe loss of white substance from the brain with a reduction in basal forebrain cholinergic neurons that can be observed in the postmortem cerebral cortex of Alzheimer’s patients [ 10 ]. The glutamatergic hypothesis is based on a gradual deterioration of adequate synaptic function through N-methyl-D-aspartate receptors that contain GluN2A and the development of excitotoxicity through NMDA receptors that contain GluN2B. If the activity of NMDA receptors is altered, amyloid-beta peptide can induce synaptic impairment, spinal loss, and neurodegeneration [ 11 ]. The mitochondrial hypothesis predicts that mitochondrial dysfunctions will trigger a deterioration of energy metabolism, producing an excess of reactive oxygen species, and consequently, will cause damage to the structure of DNA. The metabolic hypothesis assumes that mitochondrial dysregulation will increase the activity of oxidative phosphorylation [ 12 ]. The tau hypothesis is based on a tau dysfunction (abnormal levels, ubiquitination, or hyperphosphorylation) being sufficient to cause neuronal and synaptic loss. In AD, the tau protein is aggregated, forming paired helical filaments, and adopts a beta β -sheet conformation. These tangles are in areas where there is neuronal dysfunction, unlike senile plaques that appear in the brain of patients in a nonspecific and more general manner [ 13 ]. Another hypothesis is that involving protein kinase C, based on acquiring and modifying dendritic spines, in neuronal retraction and synaptic plasticity [ 14 ]. The elimination systems hypothesis is based on a failure in amyloid-beta elimination. The excessive accumulation of amyloid-beta peptides results in an imbalance between their production and their elimination in AD [ 15 ]. The neuroinflammation hypothesis is associated with an innate immune response characterized by the release of inflammatory mediators [ 16 ]. Finally, the cognitive reserve hypothesis explains the gap between brain aggression and pathological manifestations. It includes two elements: the brain (brain size, synaptic count, and dendritic branching) and the cognitive reserve (neuronal and compensatory reserve) [17]. Currently, there are no effective pharmacotherapeutic agents to prevent or treat AD. The established therapy is only reliable to treat the symptoms of the pathology [ 18 ] by normalizing the levels of neurotransmitters that are affected in AD, i.e., with treatments producing an increase in acetylcholine levels (cholinesterase inhibitor drugs) [ 19 ] and a decrease in glutamate levels (glutamate inhibitor drugs) [ 20 ]. Figure 1presents the main molecules currently used for AD treatment. The effectiveness of all these molecules varies between patients and stages of the disease, and in many cases, these drugs have adverse effects (nausea, vomiting, and diarrhea). For all these reasons, numerous efforts have been made in developing new therapeutic agents to find new drugs of value against AD [ 21 – 27 ]. It is widely known that the development of AD is linked to amyloidβ peptides and tau aggregation. Despite this, several other processes could contribute to the advance Mar. Drugs 2021,19, 373 3 of 26 of AD, and some of them could be related to protein–protein interactions [ 28 ]. In this field, new research in AD therapy highlights the need for modulating protein–protein interactions and the important role of peptides as potential drugs in the context of the cross-interactions, due to the selectivity and affinity of these molecules [ 28 ]. In addition, studies suggest that the intracellular accumulation of tau is a key factor in the memory deficits and the neurodegeneration in AD; therefore, the development of drugs aimed at tau clearance has gained attention in recent years [ 29 ]. Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) to degrade specific proteins from within cells represents a promising novel therapeutic strategy for AD and the related tauopathies [ 30 ]. As PROTACs could potentially be generated for any protein, they may be used to target tau, a natively unfolded undruggable protein. In addition, recent AD therapeutic approaches have focused on marine drug discovery. Marine organisms are capable of synthesizing different metabolites that are used to immobilize and capture prey, in addition to allowing them to defend themselves from predators [ 31 ]. These compounds range from small peptides and enzymes to highly complex secondary metabolites that show bioactivities in physiological systems such as those related to movement, circulation, and respiration. The importance of marine drugs against neurodegeneration is widely recognized [ 32 , 33 ]. In fact, some natural compounds are already in preclinical studies for AD treatment [ 34 ]. The main aim of this review is to describe the marine molecules that have the potential to become leaders in innovative drug discovery in AD as well as their isolation and the main sources for their obtention. Oceans serve as the habitat of a great diversity of organisms that live in different habitats characterized by specific physical and chemical properties such as salt and oxygen concentrations, pressure, radiation, temperature, and ocean currents. Figure 1. Chemical structures of FDA-approved drugs for Alzheimer’s disease treatment. 2. Marine Organisms Producing Compounds for Neuroprotection The oceans are the cradle of life and harbor a vast variety of marine organisms, covering 70% of the earth’s extension, being a source of primary materials and bioactive compounds with diverse applications [ 35 , 36 ]. More than 10,000 natural products of potential biotechnological interest have been isolated from marine organisms, mainly from organisms belonging to the base of the food chain (bacteria, fungi, micro- and macroalgae, gorgonians, sponges, nudibranchs, bryozoans, sea cucumbers, tunicates, and sea hares, among other marine organisms) [ 37 ]. These bioactive compounds result from the necessary adaptations that these organisms need to survive in this “primordial soup”, as secondary metabolites used in defensive/offensive mechanisms [ 38 ]. Currently, 38% of marine compounds reported as having pharmacological activity come from microorganisms such as bacteria, protozoa, fungi, and microalgae [31]. Approximately 20% are obtained from marine sponges and corals, with special emphasis on the Porifera phylum, being macroalgae, fish, mollusks, echinoderms, and coelenterates, with fewer reports on this theme [ 39 ]. In Mar. Drugs 2021,19, 373 4 of 26 this section, the main marine organisms reported as producers of novel neuroprotection molecules will be described in crescent order of complexity. 2.1. Bacterioplankton Bacteria were the primordial life forms on earth and are ubiquitous in every type of environment, even extreme ones [ 40 ]. Marine bacteria are unicellular prokaryotes, ranging from 0.5–1 µ m in size with diverse shapes and arrangements, and are considered the smallest autonomous sea organisms known [ 41 ]. They can be found as free-living or in symbiosis/parasitism relations with more complex organisms (e.g., corals, sponges, or macroalgae), and it is estimated that the oceans harbor about 10,000,000 different bacterial taxa [42]. Regarding bioactive molecules, their terrestrial counterparts have been extensively explored, as 50% of antibiotics known are derived from them, representing an area considered in decline today [ 43 ]. For this reason, bacterioplankton represent a new field of exploration and are often described as “chemical gold”, since they are considered to be an excellent source of new unexplored therapeutics with distinct applications [ 43 ]. Marine bacterial flora also has advantages in biotechnological terms, since its mass production proves to be more sustainable, more environmentally friendly, and cheaper through largescale production and fermentation processes compared to more complex organisms [ 44 – 46 ]. Due to its rapid growth and the use of cheap carbon sources, its production and industrialization are relatively advanced, involving subsequent steps described as follows. Initially, microorganisms are isolated from the natural environment using shotgun or objective approaches [44,45,47–51]. After sample collection, an appropriate culture medium for the growth of the sampled community is chosen or developed, and then subsequent isolation of pure cultures and screening of desired properties is performed [ 46 ]. Selected strains can also be improved through genetic and metabolomic engineering methodologies by identifying and introducing the gene expression sequence of the desired bioactive compound into an engineered host-microbe (e.g., S. cerevisiae or E. coli), bringing together genetic elements from two different genomes into one unit, achieving in this way the fermentation rates necessary for industrial pharmaceutical production [ 52 ]. Moreover, the heterologous expression systems combined with modern metagenomics make the possibility of tracing and discovering new bioactive compounds in bacterioplankton considered uncultivable real by giving prior access to the target microbiome genome using next-generation sequencing approaches, elaborating metagenomic libraries without the need to cultivate the microorganism in question [53,54]. 2.2. Marine Microalgae Marine microalgae are responsible for the primary production of ecosystems as eukaryotic photosynthetic beings [ 55 ]. They live freely in the water column or sediments or as photosymbionts with more complex organisms (e.g., sponges, corals, mollusks) [ 56 , 57 ]. Phytoplankton is responsible for the production of half of the atmospheric oxygen and has the capacity to use light and inorganic compounds and convert them into complex macromolecules (lipids, pigments, proteins, polysaccharides, etc.) [ 28 ]. It is estimated that there are 50,000 different species of phytoplankton that can be divided into three groups: Chlorophyta (green algae), Chrysophyta (golden-brown algae, yellow algae, and diatoms), and Pyrrhophyta (dinoflagellates), with different shapes and sizes ranging from 2 to 200 µ m [ 58 – 61 ]. As many microalgal species have short reproductive cycles, considerable amounts can be produced in closed systems, i.e., photobioreactors under controlled conditions [ 62 – 64 ]. However, the biosynthesis of valuable metabolites in considerable amounts is achieved in response to changes in environmental conditions such as nutrient availability, salinity, light, temperature, and pH. A physiological reaction to a stressor translates into a modulation in their metabolism to adapt and survive. Therefore, changes in the culturing conditions of microalgae consequently lead to an alteration in their biochemical composition that can enhance the production of target molecules of interest [ 65 – 69 ]. In this Mar. Drugs 2021,19, 373 5 of 26 sense, photobioreactors present themselves as excellent cultivation systems to improve and refine control conditions and cultivation methods, enhancing and stimulating the production of new bioactive compounds of interest [ 64 , 69 ]. Though this is promising, microalgae present some challenges, namely in terms of taxonomic identification and the fact that only a few microalgae genomes are fully sequenced and known today [ 60 , 61 , 70 , 71 ]. Despite their brief reproductive cycles, many phytoplankton species are fastidious with slow growth under controlled laboratory conditions [ 46 ]. Although the number of novel bioactive compounds of phytoplankton origin has increased in recent years, there is still much more to unravel, due to the challenging task regarding description and identification of phytoplankton and the optimization and enhancement of culture conditions to make them a sustainable and appealing source of supply [60,61,70–72]. Marine Macroalgae Marine macroalgae, more commonly known as seaweeds, are eukaryotic multicellular photosynthetic organisms that inhabit intertidal and tropical environments [ 73 ]. Based on pigment abundance, they are classified into three distinct classes: green algae (Chlorophyceae), brown algae (Phaeophyceae), and red algae (Rhodophyceae) [ 73 ]. Marine macroalgae are well known for their use in the food industry, especially in Asian countries, though their application regarding healthcare has been connected to traditional medicine [ 74 , 75 ]. So far, more than 32,000 novel compounds have been reported from macroalgae’s vast array of bioactivities and applications [ 76 – 78 ] Regarding the extraction of these compounds, new green approaches have gained strength in recent years. They are characterized by the reduction in the number and amount of solvents, faster extraction times, good performance at low temperatures, good selectivity towards the targeted compound, and prevention of undesired reactions and byproducts during extraction, having for these reasons gained more followers compared to traditional extraction techniques [79]. Among these green innovative extraction techniques applied in the isolation of bioactive compounds from marine macroalgae are microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), pressurized liquid extraction (PLE), and supercritical fluid extraction (SCFE) [ 80 – 82 ]. UAE is based on the application of ultrasound waves above 20 kHz to create bubbles and zones of high and low pressure [ 83 ]. MAE uses microwaves to heat the samples, evaporating the intracellular fluids [ 84 , 85 ]. PLE is a technique based on the use of conventional solvents at temperatures and pressures high enough to maintain the solvent in the liquid state during the whole extraction procedure [ 86 , 87 ]. Finally, SCFE uses a supercritical fluid as a solvent. It is based on the principle of extraction with fluids in their supercritical conditions, where temperature and pressure are raised above their critical point, with characteristics of both liquids and gases. However, the exploration of necessary macroalgae to conduct clinical trials can have a huge impact on marine ecosystems’ sustainability. Moreover, the composition of bioactive compounds has species-specific variation and is dependent on several parameters such as organism age and size, predation pressure, tissue type, and abiotic factors [ 88 ]. The development of efficient culture approaches is mandatory to prevent pressure and overexploitation of natural populations [88]. 2.3. Marine Sponges Marine sponges are multicellular invertebrate sessile organisms that belong to the Porifera phylum; they have a wide distribution, being able to colonize different kinds of habitats in terms of temperature, salinity, and pressure [ 89 ]. As their name implies, these organisms have a soft body composed of cell layers that house the spicule skeleton, composed of a protein known as spongin, calcium carbonate, and silica, and the identification of these animals is determined by characterizing the size and shape of these spicules [ 90 , 91 ]. So far, approximately 15,000 different species have been cataloged [ 91 ]. Sponges are sessile filter feeders; their simple structure of channels allows them to feed on the microorganisms and matter in water that circulates through their bodies. However, this particular condition Mar. Drugs 2021,19, 373 6 of 26 also exposes them to potentially hazardous particles, infectious agents, and predators, forcing them to cope with these external threats by developing strong chemical defense mechanisms [91]. Here the story of new marine bioactive compounds begins in 1950 when spongothymidine and spongouridine, nucleosides that led to the synthesis of the first antiviral drug, were primarily isolated from T. crypta, a tropical specimen [ 92 ]. Since then, hundreds of new chemically diverse bioactive compounds have been reported from several sponge genera [ 93 ]. Sponges are reported to synthesize a wide range of compounds, including nucleosides, alkaloids, cyclic peptides, sterols, and terpenes [ 94 ]. Nevertheless, the credit for the new compounds cannot be given to sponges alone, since they are symbiont beings, sheltering a microbial flora that provides a chemical defense to its host by the production of secondary metabolites. Thus, most of the discoveries in sponges on this theme have origin in their symbionts [ 95 ]. This is not discouraging, since the conditions for cultivation and maintenance of these animals are challenging and need improvement, and it is not environmentally sustainable to obtain specimens from nature to feed this type of research. Therefore, the discovery of new bioactive compounds through sponges can rely on metagenomic methods described above to obtain crude extracts that can be fragmented and purified with aid from the new green approaches previously mentioned [96]. 2.4. Marine Tunicates Tunicates, also known as ascidians belong to the Urochordate subphylum, are characterized by their vertebrate-like larval free stage contrasting with their sessile invertebrate adult stage [ 97 ]. Tunicates have sexual and asexual reproduction and have varied phenotypes; they are also the only animals known for the production of cellulose, and up to now about 3000 species have been described [ 97 ]. The drug discovery in ascidians began in the 1960s with the discovery of the antiviral and antitumor geranyl hydroquinone, isolated from the tropical genus Trididenium [ 98 ]. Since then, 1200 natural compounds have been identified from this subphylum [ 99 ]. As mentioned, tunicates are sessile in their mature stage and have been reported to be the home of a diverse microbial community [ 100 , 101 ]. In this sense, some of the new compounds of biotechnological interest first identified in tunicates were later reported as originating from their associated symbiotic flora [ 102 , 103 ]. Techniques such as highly advanced analytical tools, new methods for genetic and chemical dereplication, molecular biology tools, LC-MS, and NMR metabolomics approaches, combined with efforts of computational biology, have directed and increased the highthroughput screening efficiency of exploring novel therapeutics in tunicates [104–107]. 2.5. Marine Arthropods Crustaceansarea large arthropod subphylum, consisting of more than 52,000 species [ 108 ]. They are the oldest arthropods, from which insects evolved, and are characterized by their chitinous exoskeleton [ 108 ]. Crustaceans are considered a valuable nutritional source and play a huge economical role in fishery and aquaculture industries today [ 109 , 110 ]. The exploration of bioactive compounds from this subphylum is quite recent and motivated by the use of food waste. One of the first approaches occurred in 2013 with the purification of a peptide (CMCC-1) with antimicrobial activity [ 111 ]. Subsequently, several studies followed this trend mainly in the study of the main constituent of the exoskeleton of these arthropods, chitin, due to its abundance in the remains of the food industry, bioavailability, structural stability, and safe handling [ 112 ]. Chitin is relatively simple to extract with a four-step approach that comprises demineralization, deproteinization, decolorization, and oxidation [ 113 ]. From it is derived one of the most popular molecules with crustacean origin, chitosan, which will be discussed in more detail in the following sections. The use of marine-based foods remains a sustainable alternative, still little explored, for the search for new bioactive compounds and should be stimulated. Mar. Drugs 2021,19, 373 7 of 26 3. Marine Compounds against Alzheimer’s Disease: From Sea to Cells The continuously growing interest in marine-derived molecules is justified by the structural properties that are not usually found in terrestrial organisms, exhibiting considerable bioactivity, up to ten times higher than that of terrestrial-sourced compounds [ 22 ]. In this section, we describe the mechanisms of action of the main compounds isolated from marine organisms with neuroprotection activity against AD, as summarized in Table 1. Table 1. Main natural marine compounds with pharmacological activity to treat AD. Compound Origen Family Mechanism of Action Ref. Sponges Gracilins Marine sponges (Spongionella gracilis) Diterpenoid derivatives Inhibition of the enzyme b-secretase or BACE-1. Anti-inflammatory and antioxidant properties. Reduction in hyperphosphorylation of tau protein. [39] Manzamines Marine sponges (Haliclona sp. Alkaloids with beta-carboline structure Inhibition of GSK3beta and CDK5. [114] Macroalgae and microalgae Fucoidans Brown seaweeds Sulfated polysaccharides Block caspase-9 and caspase-3 enzymes. [115] Phlorotannins Brown seaweeds (Ecklonia cava,Ecklonia stolonifera) Polyphenols Inhibition of the enzymes acetylcholinesterase and butyrylcholinesterase. [116] Homotaurine Red seaweeds Aminosulfonate Prevention of the formation of a toxic soluble amyloid oligomer. [117] Spirolides Alexandrium ostenfeldii/peruvianum dinoflagellates Cyclic imines Decrease GSK-3βand ERK in 3xTg mice cortical neurons. Glutamate-induced neurotoxicity inhibition both in control and 3xTg neurons. [118] Bacteria Caniferoles Phylum Actinobacteria Polyol macrolides Anti-inflammatory and antioxidant action. Blockade of the BACE-1 enzyme. [25] Marine invertebrates, crustaceans, tunicates Bryostatins Brown bryozoa (Bugula neritina)Macrolide lactones Modulates neuronal synapses under synaptic dysfunctions; improvement of memory, cognition, and spatial learning; decreases amyloid-beta peptide; reappearance of neurotrophic activity. [119,120] Chitosan Crustaceans Polysaccharides Inhibition of the enzyme acetylcholinesterase. [121] Meridianins Tunicates (Aplidium meridianum)Alkaloid indols Inhibition of GSK3beta, CK1sigma, DYRK1A, and CLK1. [122,123] Abbreviations: beta-secretase enzyme (BACE); cyclin-dependent kinase 5 (CDK5); glycogen synthase kinase 3 beta (GSK-3 β ); extracellular signal-regulated kinase (ERK); dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); cell division cycle 2-like kinase 1 (CLK1). 3.1. Gracilins Gracilins are sponge-derived diterpenoids isolated from marine sponges. The first analog structurally elucidated was gracilin A (Figure 2A), discovered in 1985 and isolated from the Mediterranean sponge Spongionella gracilis [ 124 ]. This was followed by the isolation of gracilin B and gracilins G–I from Spongionella pulchella [ 125 ] and gracilins J–L [ 39 ]. Gracilin A was described to have the most potent immunosuppressive and neuroprotective activity of all analogs. All of them have in their structure the group diacetoxyhexahydrodifuro [2,3-b;3,2-d]furan-2-one, a moiety that is uncommon in nature [ 27 ]. These compounds can inhibit the beta-secretase 1 enzyme, the kinase enzyme regulated by extracellular signals, and reduce the hyperphosphorylation of the tau protein [ 27 ]. Gracilins generate a neuro- Mar. Drugs 2021,19, 373 8 of 26 protective effect on primary neurons with restored mitochondrial membrane potential and inhibition of alterations produced by the classical uncoupler of mitochondrial oxidative phosphorylation carbonylcyanide-p-trifluoromethoxyphenylhydrazone [ 126 ]. Moreover, they can enhance the expression of nuclear factor erythroid 2-related factor 2 (NRF2), which is involved in the activation of the antioxidant pathway. The antioxidant properties are responsible for the specific interactions of gracilins with the jaws proteins which are involved in apoptosis or the Nrf2-Keap1-ARE signaling pathway, ensuring their mechanism of action on Nrf2 levels in the nucleus [ 123 ]. In addition, gracilins have an important anti-inflammatory action, due to their ability to inhibit the enzyme phospholipase A2 (PLA2), which can reduce the production of reactive oxygen species (ROS) induced by amyloid-β[127]. Figure 2. Chemical structure of marine molecules with neuroprotective effects against Alzheimer’s disease: gracillin A ( A ), manzamine A ( B ), fucoidan ( C ), eckol ( D ), homotaurine ( E ), 13-desmethyl spirolide C ( F ), caniferolide A ( G ), bryostatin-1 (H), chitosan (I), chitin (J) and meridianin A (K). Mar. Drugs 2021,19, 373 9 of 26 3.2. Manzamines Manzamines are alkaloids characterized by the presence of a β -carboline structure attached to a pentacyclic diamine ring, having 8- and 13-membered rings on a pyrrolo[2,3- i]isoquinoline framework [ 128 ]. Manzamine A (Figure 2B) was isolated for the first time from the marine sponge Haliclona sp. in 1986 [ 129 ]. Its activity to inhibit the GSK3beta enzyme noncompetitively was later discovered by in vitro studies when it was observed that an increase in the concentration of ATP did not cause a change in its inhibitory activity. Today, more than 100 analogs have been characterized, and it is likely that many more remain to be tested in medicinal chemistry studies [ 130 ]. Manzamine A can bind to a pocket close to the catalytic region of GSK3beta, inhibiting the enzyme allosterically [ 114 ]. The inhibitory capacity of manzamines on GSK3beta and other kinases was evaluated in a study carried out in human neuroblastic cells, and it was found that manzamine A is the only analog capable of inhibiting GSK3beta and CDK5. Likewise, the treatment of SH-SY5S cell cultures with different concentrations of manzamine A resulted in a decrease in the phosphorylation of the epitope Ser 396 of tau, which is specifically phosphorylated by GSK3beta [114]. 3.3. Fucoidan Fucoidan (Figure 2C) is a sulfated polysaccharide-type compound extracted from brown seaweeds [ 131 ]. Structurally it is composed of a backbone of alpha(1 → 3)-L-fucopyranose or L-fucopyranosyl residues linked to alternate alpha(1 → 3) and alpha(1 → 4). Fucoidan is reported to act on different stages of the inflammatory process [ 132 ]. It blocks the lymphocyte adhesion and invasion, inhibits the multiple enzymes, and induces apoptosis [ 132 ]. Fucoidan can block the activation of the enzymes caspase-9 and caspase-3, suggesting that the inhibition of neuronal death by this compound mainly occurs through the inhibition of apoptosis since these enzymes play an important role in apoptosis processes [ 115 ]. A fucoidan treatment has been found capable of reducing the inhibitory effect of amyloid-beta on protein kinase C (PKC) phosphorylation [ 133 ]. Fucoidan can prevent amyloid-beta neurotoxicity and stimulate neuronal survival. Protein kinase C produces an inactivation of GSK-3b and, in turn, an accumulation of cytoplasmic beta-catenin in the nucleus which causes the TCF/LEF-1-dependent transcriptional activation of genes that are related to growth and the differentiation that is needed to stimulate the survival of neurons [ 133 ]. Recently, it was also demonstrated that fucoidan is a neuroprotective agent in a mouse model of AD [ 21 ]. The compound showed neuroprotective effects against A β - and D-Gal- induced apoptosis in PC12 cells and D-Gal-induced learning and memory impairment in AD model mice. The related mechanisms comprise the regulation of the cholinergic system, oxidative stress reduction, and the inhibition of the caspase and mitochondria apoptosis pathways [21]. 3.4. Phlorotannins Phlorotannins are polyphenols that can be found in the brown algae species Ecklonia cava, Ecklonia stolonifera, and Eisenia bicyclis [ 130 ]. Phlorotannins such as phlorogucinol, eckol, dieckol, phloroeckol, and phlorofurofucoeckol are related to an increase in the most important central neurotransmitter in the brain, the neurotransmitter acetylcholine, by inhibiting the activity of the enzymes acetylcholinesterase and butyrylcholinesterase. The structure of eckol is represented in Figure 2D. Eckol, dieckol, and 8,8 0 -bieckol from Ecklonia cava can inhibit the BACE-1 enzyme [ 116 ]. The drugs currently used for the AD treatment mainly act by inhibiting the enzyme acetylcholinesterase, so the discovery of the inhibition of the BACE-1 enzyme by phlorotannin may improve the drugs and treatment for patients affected by AD. Recently, it was shown for the first time that the phlorotannin dieckol regulates APP proteolytic processing and A β production via the regulation of the PI3K/Akt/GSK-3 β signaling pathway [ 134 ]. Moreover, the addition of LY294002 counteracts all the effects of dieckol, demonstrating that Akt/GSK-3βis the primary pathway mediating Aβproduction in SweAPP N2a cells. Mar. Drugs 2021,19, 373 16 of 26 Table 2. Cont. Compound Specie Extraction/Isolation Method Quantity Yield (%) Ref. Homotaurine Botryocladia leptopoda (1 g) S-L extraction: 10 mL ethanol 70–80% (v/v). Centrifugation (4000 rpm, 10 min). Collect the supernatant. 32.3 µg/g 0.0032% [173,174] Homotaurine Gelidium micropterum (1 g) 32.5 µg/g 0.0032% [173,174] Homotaurine Caulerpa racemosa (1 g) 10.56 µg/g 0.001% [173,174] Homotaurine Cystoseira indica (1 g) 5.05 µg/g 0.0005% [173,174] Homotaurine Hypnea boergesenii (1 g) 702.7 µg/g 0.0702% [173,174] Homotaurine Gracilaria corticata (1 g) 474.9 µg/g 0.0474% [173,174] Homotaurine Gracilaria pygmaea (1 g) 333.5 µg/g 0.0333% [173,174] Homotaurine Sargassum tenerrimum (1 g) S-L extraction: 10 mL ethanol 70% (v/v). 6.54 µg/g 0.0006% [74] Homotaurine Dyctiota dichotoma (1 g) 14.62 µg/g 0.0014% [74] Homotaurine Gracilaria arcuata (1 g) 6.48 µg/g 0.0006% [74] 13-Desmethyl spirolide C and Alexandrium ostenfeldii (24 cultures of 20 or 40 L) S-L extraction: MeOH. L-L extraction: CH2Cl-H2O. Clean up: Sephadex LH-20. Purification: HPLC preparative: Vydac column 201TP C18, F.M. acetonitrile/water (30:70) + 0.1% TFA. 150 µg - [180] 13,19-Didesmethyl spirolide C 1 mg - [180] Source: Bacteria Caniferolides A Streptomyces caniferus CA-271066 (2.3 g appox) Pretreatment: acetone. L-L extraction: ethyl acetate/water. Clean-up: Sephadex LH-20. Purification: Semipreparative reversed-phase HPLC (Agilent Zorbax RX-C8), M.P.: CH3CN/H2O. Semipreparative reversed-phase HPLC (XBridge C-18) (only for caniferolide D). 10.0 mg 0.43% [25,181] Caniferolides B 3.6 mg 0.16% [25,181] Caniferolides C 4 mg 0.17% [25,181] Caniferolides D 1 mg 0.043% [25,181] Caniferolide C Streptomyces sp. ISID311 (1 L of culture) crude extract (2.3 g) Pretreatment: acetone. L-L extraction: ethyl acetate/water. Clean-up: SPE-C18 (55 µm, 20 g). Purification: semipreparative HPLC. 14.2 mg 0.62% [182] Crustaceans Chitosan Shell power (1 g) Demineralization: 1 M HCl at 60 ◦C (30 min). Deproteinization: 3 M NaOH at 80 ◦C (120 min). 350 mg 35% [185,186] Meridianins A–G Aplidium falklandicum and Aplidium meridianum Clean-up: Sephadex LH-20 and silica gel columns. Purification: with TLC using preparative (SiO2) plates and HPLC (reversed-phase semipreparative C18 columns). 19.11 mg/g DW 1.91% [148] Abbreviatures: acetonitrile (MeCN); buthanol (BuOH); ethyl acetate (EtOAc); ethanol (EtOH); liquid–liquid (L-L); microwave-assisted extraction (MAE), methanol (MeOH); mobile phase (M.P.); phloroglucinol equivalents (PGE); phlorotannin content (PC); phlorotannin derivatives (PD); pressurized-liquid extraction (PLE); retention time (RT); solid–liquid (S-L); ultrasound-assisted extraction (UAE). 5. Challenges and Opportunities in the Exploitation of Marine Molecules to Manage Alzheimer’s Disease AD constitutes one of the main social and health challenges of the XXI century with high prevalence and incidence rates, which will gradually increase due to the aging of the population [ 3 ]. Therefore, finding robust and viable lead candidates in drug discovery to manage AD is a challenging but important scientific task. At present, the benefits produced by the marine bioactive molecules to exert neuroprotection and reviewed in this paper are being considered by several research groups. Compounds such as tramiprosate or bryostatin-1 are in the clinical phase. In addition, gracilins and caniferolide A have shown relevant results [ 25 , 39 ]. However, testing the pharmacological effects of novel molecules is only the first step in the drug discovery process. The hardest challenge is turning these products into useful drugs due to the high costs of releasing a new medicine to market from discovery through a clinical phase to approval. Another major challenge is to reduce the time taken to approve these products for use, which is nowadays approximately 10 years [ 189 ]. In addition, the extraction, isolation, and characterization of molecules Mar. Drugs 2021,19, 373 17 of 26 from marine sources are crucial steps of drug discovery. The industry has to invest in all these technological processes and cope with the fact that these processes do not guarantee the successful outcome of the investment. Despite growing developments in isolation methods, extraction of natural products from sponges, microalgae, and marine bacteria is still a challenging task. It has become difficult to extract and purify the scarcer novel minor secondary metabolites [151]. Comparing gracilins and manzamines, both obtained from sponges, yields from the latter are extremely low, for example, 0.00038% for manzamine A, making their purification quite unviable at a large scale. Gracilins are obtained in higher quantities ranging from 0.18 to 2.3%, and caniferolides, obtained from Streptomyces bacteria, are yielded in the range 0.043–0.62%. Comparing compounds from macroalgae (homotaurine, fucoidans, and phlorotannins), results revealed that it is not worth naturally extracting homotaurine. Although red algae (Hypnea boergesenii,Gracilaria corticate, and Gracilaria pygmaea) are the main producers of homotaurine, yields are lower than 0.0702% [ 173 , 174 ]. On the other hand, the extraction of fucoidans and phlorotannins from seaweeds constitutes a feasible process. It is possible to obtain fucoidans derived from Sargassum siliquosum in quantities of 35 mg/g (3.5%) [ 157 ], and phlorotannins are in levels around 63.61 mg PGE/g in Sargassum fusiforme (yield of 6.36%) [ 165 ]. However, to ensure progress in this field, still there is a need for determining the reproducible and well-characterized chemical composition of these molecules. For example, fucoidan fractions can vary considerably according to the natural source. These molecules can represent an enormous opportunity for the biomedical market if alternative methods to produce fucoidans with consistent properties can be developed, since these properties critically influence biological activities [ 190 ]. As said before, the low quantities of bryostatins in bryozoans (0.00014%) make extraction unviable for large-scale production [ 143 ]. On the contrary, chitosan is abundant in nature; its extraction from shells is possible, obtaining yields of 35%. Regarding the obtention of spirolides from microalgae, they can be obtained in limited amounts from contaminated shellfish, so it would be necessary to develop large-scale methods for the extraction of these toxins from phytoplankton samples [ 178 ]. In this context, an integrated approach involving high-productivity cultivation and efficient harvesting can help advance the status of microalgae technologies. Extraction of biochemical components of interest from microalgae requires cell disruption and fractionation methods. Finally, meridianins A–G are obtained in quantities of 19.1 mg/g (1.91%). For all these molecules, the supply problem could be solved by processes of marine biotechnology (aquaculture/mariculture/fermenter cultivation, genetic engineering, enzymatic synthesis or modification) or by chemical synthesis/semisynthesis/modification [ 191 ]. In addition, the development of new extraction technologies has revolutionized the screening of natural marine products (specially macroalgae) in discovering new drugs. Applying these technologies offers a unique opportunity to re-establish natural products as a major source for drug discovery. Alboofetileh et al. employed conventional and different innovative extractions, using water as the solvent, to obtain fucoidans from Nizamuddinia zanardinii. Conventional extraction showed an extraction yield of 5.2% (DW). MAE and PLE achieved higher rates, 6.17% and 13.15%, respectively [ 83 ]. The emerging extraction techniques display some advantages when extracting secondary metabolites from cells. The growth and collapse of the bubbles created in UAE break the cell walls and particles, improving the extraction by increasing the contact between the sample and the solvent. It works at low temperatures, which allows the preservation of thermolabile compounds [ 85 , 157 , 162 ]. MAE, based on the use of microwaves to heat the samples, causes the evaporation of the intracellular fluids, providing an increase in pressure that breaks the cell and consequently releases intracellular compounds into the solvent. Compared to S-L extraction, MAE reduces the amount of solvent necessary and improves efficiency [ 84 , 85 ]. PLE uses less solvent, is performed in a shorter period, is automated, and involves retaining the sample in an oxygen and light-free environment in contrast to traditional organic solvent extraction [ 192 ]. Finally, SCFE brings some advantages. When a fluid is taken above its Mar. Drugs 2021,19, 373 18 of 26 critical temperature and pressure, it exists in a condition referred to as a supercritical state. For example, carbon dioxide, once pressurized, can act as an effective solvent of nonpolar compounds. SCFE is finding increased and widespread use in the extraction from solids and liquids of such compounds with novel use as nutraceuticals and pharmaceuticals. 6. Remarks and Future Perspectives This review explores the use of sponges, algae, and other marine species to obtain molecules of high potential value with evidence-based health benefits against AD and their isolation by chromatographic and emerging extraction techniques. A critical point in the process of drug development from marine organisms and often a bottleneck is the need to obtain permanent availability of sufficient amounts of organisms and compounds without harming the marine environment. Only if supply can be addressed in an economically and ecologically feasible fashion will marine drugs reach the market [ 191 ]. The reviewed literature shows that macroalgae constitute a cost-effective and useful source for recovering phlorotannins and fucoidans with high potential for innovative biomedical applications. Chitosan has also attracted a great deal of attention in health applications due to the distinctive pharmacological and physicochemical characteristics of this molecule, which can be extracted from crustacean waste and contribute to a sustainable recovery process. In this context, environmentally friendly processes that combine various microbial, chemical, enzymatic, and membrane strategies and technologies to extract and purify chitin and chitosan from marine byproducts were also investigated [193]. One of the most promising molecules to manage AD is bryostatin-1, which is in the clinical phase. However, synthetic molecules are used as the supply for clinical trials. In preclinical studies, bryostatin-1 was found to improve memory and learning for prolonged periods, produce neuroprotective effects in transgenic mice with AD, inhibit phosphorylation of the tau protein by inhibiting the enzyme GSK3beta, prevent neuronal apoptosis, decrease amyloid-beta levels in the Tg 2576 mouse with AD, recover neurotrophic activity and loss of synapses, and improve synaptogenesis, recovering cognitive deficits [119,120,183,194,195]. Besides these compounds, gracilins and caniferolide A, obtained from natural sources (Sponginella sp. sponges and Streptomyces caniferus, respectively), have shown satisfactory results. After chronic intraperitoneal treatment of gracilins in 3xTg-EA mice, it was observed that gracilins H and L can produce an improvement in cognition [ 39 ]. Gracilin L is the only one capable of inhibiting the BACE-1 enzyme in vitro and in vivo , and gracilins H and L decrease the levels of Ab42 and phosphorylated tau protein in vivo . In general, gracilins reduce phosphorylation of tau protein by inhibiting ERK in vitro [ 27 , 39 , 125 , 127 ]. Parallelly, caniferolide A modulates the state of the microglial cell towards the phenotype of neuroprotection by causing the blockade of the kinases NFKR, p38, and JNK MAPK. This macrolide was also able to decrease the phosphorylation of the tau protein by inhibiting the p38 and JNK kinases, and through the translocation of Nrf2 to the nucleus, it acts as an indirect antioxidant [ 25 , 182 ]. This compound is also capable of inhibiting the BACE-1 enzyme, which participates in the processing of amyloid-beta. The oceans can therefore provide us with many invaluable benefits and services, including some of the medicines we use to manage AD. Even so, research on compounds of marine origin for the treatment of AD should continue in the search for new drugs with significant neuroprotective activity. A better understanding of the potential health benefits from marine organisms, the compounds they produce, and the environmental conditions affecting their production will allow for the better management and sustainable development of these valuable marine resources in the future [189]. Although great advances have been achieved in a short time in discovering new molecules, the riskiest development stages of a potential drug (production optimization, safety studies, and clinical trials) are assumed by the academic world or small biotechnology laboratories. To continue to give answers to human needs, more investment in biotechnology should be encouraged and stimulated. Mar. Drugs 2021,19, 373 19 of 26 Author Contributions: Conceptualization, P.O.; methodology, P.O., M.S. and P.S.; formal analysis, P.O. and M.S.; investigation, P.O., M.S. and P.S.; writing—original draft preparation, P.O., M.S. and P.S.; writing—review and editing, P.O.; visualization, P.O.; supervision, P.O.; funding acquisition, M.S. and P.O. All authors have read and agreed to the published version of the manuscript. Funding: P.O. would like to thank the Juan de la Cierva program of the Spanish Government (Ref. IJCI-2016-27774). M.S. would like to thank Fundação para a Ciência e a Tecnologia (FCT) for research funding via the VALTOX project under UIDB/04292/2020 and UID/MULTI/04046/2019 and was also supported by investigation contract under AQUA-PROSPECT project (MAR-02.02.01-FEAMP-0005). Institutional Review Board Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. References 1. 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