International Journal of Molecular Sciences Review Natural Compounds for Alzheimer’s Disease Therapy: A Systematic Review of Preclinical and Clinical Studies Stephanie Andrade, Maria João Ramalho , Joana Angélica Loureiro * and Maria do Carmo Pereira * LEPABE, Department of Chemical Engineering, Faculty of Engineering of the University of Porto, 4200-465 Porto, Portugal; [email protected] (S.A.); [email protected] (M.J.R.) * Correspondence: [email protected] (J.A.L.); [email protected] (M.d.C.P.) Received: 16 April 2019; Accepted: 7 May 2019; Published: 10 May 2019 Abstract: Alzheimer’s Disease (AD) is a neurodegenerative disorder related with the increase of age and it is the main cause of dementia in the world. AD affects cognitive functions, such as memory, with an intensity that leads to several functional losses. The continuous increase of AD incidence demands for an urgent development of effective therapeutic strategies. Despite the extensive research on this disease, only a few drugs able to delay the progression of the disease are currently available. In the last years, several compounds with pharmacological activities isolated from plants, animals and microorganisms, revealed to have beneficial effects for the treatment of AD, targeting different pathological mechanisms. Thus, a wide range of natural compounds may play a relevant role in the prevention of AD and have proven to be efficient in different preclinical and clinical studies. This work aims to review the natural compounds that until this date were described as having significant benefits for this neurological disease, focusing on studies that present clinical trials. Keywords: neurodegenerative disease; bioactive compound; natural extract; β-amyloid peptide; tau protein; clinical trial; human studies; animal studies; in vitro studies 1. Introduction Neurodegenerative diseases induce alterations in the central nervous system with psychological and physiological negative effects [1]. Alzheimer’s disease (AD) is known as a neurodegenerative disorder with major importance and the principal cause of dementia among the elderly [2,3]. Microscopically, intraneuronal neurofibrillary tangles (NFTs) and extracellular senile plaques (or amyloid plaques) characterize the AD. While senile plaques are constituted by extracellular deposits of β-amyloid (Aβ) peptide, the hyperphosphorylation and abnormal deposition of tau protein compose the NFTs [4]. Aβ derives from the amyloid precursor protein (APP), proteolytic cleavage of amyloid precursor protein (APP), an integral membrane protein that possesses the general properties of a cell surface receptor [5], by the consecutive action of β- and γ-secretases (amyloidogenic pathway). However, this amyloidogenic pathway can be stopped by the competition of α-secretase with γ-secretase (non-amyloidogenic pathway) [6]. The amyloid cascade hypothesis (ACH) suggests that the imbalance between the Aβ generation and its clearance causes the dysfunction and consequently cell death. Aβ polymerizes in a variety of structurally different forms including oligomeric, protofibrillar, and fibrils, forming the senile plaques [7]. Several findings suggest that oligomers play an important role in the ACH [8]. Nowadays, it is proved that Aβ oligomers, including protofibrils and prefibrils, are more toxic than fibrils [9]. Tau protein is also related with the ACH. First, tau monomers aggregate and form oligomers that aggregate into a β-sheet conformation, forming NFTs [10]. NFTs accumulate Int. J. Mol. Sci. 2019, 20, 2313; doi:10.3390/ijms20092313 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 44 Int. J. Mol. Sci. 2019, 20, 2313 2 of 41 monomers aggregate and form oligomers that aggregate into a β-sheet conformation, forming NFTs [10]. NFTs accumulate inside the neurons, resulting in their death. The ACH suggests that toxic inside the neurons, resulting in their death. The ACH suggests that toxic concentrations of Aβ cause concentrations of Aβ cause changes in tau protein and subsequent formation of NFTs, leading to changes in tau protein and subsequent formation of NFTs, leading to synaptic and neuronal loss [11]. synaptic and neuronal loss [11]. Though a direct relationship between the degree of AD and the Though a direct relationship between the degree of AD and the amount of Aβ aggregates and tau amount of Aβ aggregates and tau levels have been established, numerous other mechanisms of levels have been established, numerous other mechanisms of neurodegeneration have been suggested, neurodegeneration have been suggested, such as neuroinflammation [12], oxidative stress [13], such as neuroinflammation [12], oxidative stress [13], genetic [14] and environmental factors [15]. So, genetic [14] and environmental factors [15]. So, there is an urgent need to develop efficient therapies there is an urgent need to develop efficient therapies that target the various pathogenic mechanisms that target the various pathogenic mechanisms associated with AD. Based on these mechanisms, associated with AD. Based on these mechanisms, different therapeutic molecules can act through different therapeutic molecules can act through different pathways [16–18]. However, the currently availabledifferent pathwaysmedications [16 only–18]. cont However,rol the thesymptoms currently in availablean early stage medications of the disease only control [11]. the symptoms in anTherefore, early stage it of is the fundamental disease [11]. to seek for new strategies for AD therapy [19–22]. Natural compoundsTherefore, were it isthe fundamental first molecules to seek used for as new therap strategieseutic foragents AD therapy[23]. Nowadays, [19–22]. Natural the study compounds of these naturalwere the compounds first molecules revealed used that as therapeuticthey present agents neuroprotective [23]. Nowadays, effects, the arousing study of an these increasing natural interestcompounds in the revealed scientific that community they present and neuroprotective in the pharmaceutical effects, arousing industry an increasing[24,25]. A interest diversity in theof naturalscientific compounds community from and indifferent the pharmaceutical origins was industrydescribed [ 24to, 25be]. suitable A diversity to prevent of natural and compounds attenuate severalfrom di pathologies,fferent origins including was described neurological to be diseases, suitable such to prevent as AD [26–28]. and attenuate Several severalin vitro pathologies,and in vivo studiesincluding have neurological proven the diseases, therapeutic such as ADpotential [26–28 of]. Severalnaturalin compounds, vitro and in vivohowever,studies just have a provensmall percentagethe therapeutic has reached potential the of clinical natural trials compounds, stage [29]. however, Since several just acauses small are percentage related with has this reached disease, the theclinical preventive trials stage properties [29]. Since of the several natural causes compound are relateds can with be thisassociated disease, with the preventiveseveral mechanisms properties as of shownthe natural in Figure compounds 1 [6,30–34]. can be associated with several mechanisms as shown in Figure1[6,30–34]. Figure 1. Schematic representation of the several mechanisms associated with Alzheimer’s Disease Figure(AD) therapy. 1. Schematic Down representation and up oriented of arrowsthe several indicate mech theanisms decrease associated and the with increase Alzheimer’s of the fenomena, Disease (AD)respectively. therapy. Down and up oriented arrows indicate the decrease and the increase of the fenomena, respectively. In this review, the natural compounds already in clinical trials phase are described and the reported resultsIn arethis presented review, andthe discussed.natural compounds Other natural already compounds in clinical with knowntrials phase potentially are described beneficial effectsand the in reportedAD in a preclinical results are development presented stageand discussed. with in vitro Otandher innatural vivo studies compounds are also with described. known For potentially preclinical beneficialstudies, only effects the mostin AD recent in a preclinical reported works development are cited. stage The systematicwith in vitro literature and in searchvivo studies was conducted are also described.using PubMed, For preclinical Science direct, studies, Google only Scholar, the most Scopus recent andWeb reported of Science works as onlineare cited. databases The systematic until April literature2019. Only search papers was written conducted in English using were PubMed, considered Science with direct, unlimited Google publication Scholar, Scopus date. and Web of Int. J. Mol. Sci. 2019, 20, 2313 3 of 41 2. Natural Compounds in Clinical Trials and Their Effects on AD Natural compounds are an emerging approach for AD therapy. For the assessment of their therapeutic efficiency and potential side effects, human trials have been performed in the last years. The first natural product studied in a clinical trial was nicotine in 1992. However, no clinical trials were performed in the last two decades for this molecule. During the 90s, several other compounds were studied in clinical trials for AD therapy, such as vitamins. These molecules are still being tested in human trials up until this date. In the last years, other natural compounds are gaining interest by the scientific community and have achieved the clinical trials phase, such as bryostatin, which effects started to be evaluated in humans in 2017. A detailed report of these findings is described