Alzheimer’s disease (AD), the leading cause of dementia, is a progressive neurodegenerative disease that is clinically characterized by memory loss, cognitive impairment, and behavioral disturbances [2]. Since its discovery in 1906, AD has emerged as one of the most costly, fatal, and burdensome diseases of this century [3]. The pathogenesis of AD involves various biological processes [4] involving the abnormal deposition of amyloid beta peptide (Aβ) [5], the accumulation of neurofibrillary tangles (NFTs) [6], neuroinflammation [7], neuronal apoptosis [8], neurotransmitter abnormities [9], and oxidative stress [10]. Despite considerable efforts, drug discovery for the treatment of AD has been slow, with only acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitors [11] such as galantamine, donepezil, tacrine, and rivastigmine currently available as therapies [12]. However, these treatments only delay the onset of symptoms and cannot halt disease progression and are often associated with significant side effects [13]. Therefore, the development of new therapeutic drugs is urgently needed. Saponins, a type of natural compound, have been extensively studied for their various pharmacological properties [14]. Of particular interest is their potential to enhance learning and memory in individuals with AD [15].

Saponins are naturally occurring compounds that are widely distributed in various plants [16], and they can be divided into two major groups based on their chemical structure: triterpenoid saponins and steroidal saponins [17]. Triterpenoid saponins are further subdivided into tetracyclic triterpenes and pentacyclic triterpenes and are mainly found in plants such as Pentaaceae, Leguminosae, Poria, and Platycodonaceae [18]. The main saponin skeletons of the triterpenoid saponins include dammarane, oleanane, ursane, and lupane (Figure 1 A, B, C, D) [19]. Steroidal saponins, on the other hand, are mainly found in plants such as Dioscoreaceae, Liliaceae, and Scrophulariaceae [20]. The main saponin metaskeletons of steroidal saponins include spirostane, furostane, cholestane, and cardenolide (Figure 1 E, F, G, H) [21]. Saponins possess multiple bioactivities, such as reduction of amyloid beta (Aβ) deposition [22], inhibition of tau protein phosphorylation [23], antioxidation [24], antiapoptosis [25], and anti-inflammation [26]. These properties make saponins promising therapeutic candidates for AD and other neurological disorders [27]. Meanwhile, the diversity of saponins found in different plants [28] makes them a valuable source of potential drugs for the treatment of AD. However, there is a current lack of comprehensive and systematic review in this field. To address this gap, we thoroughly searched the relevant literature in the major databases, including PubMed and Web of Science, using keywords “Alzheimer’s disease” or “AD” and “saponin”. By browsing all the relevant studies from May 2007 to May 2023, excluding review articles, 63 references were selected, involving 40 saponins extracted from different herbs. The selected references are known to be effective in the treatment of AD, present clear mechanisms, authentic and reliable information, and contain the latest findings in the field. The studies highlighted that saponins have exhibited various beneficial effects such as reducing Aβ levels, reducing NETs, exerting antioxidative, antiapoptotic, anti-inflammatory, and increased neurotransmitter-enhancing effects [25]. The underlying mechanisms behind these effects include reducing amyloid precursor protein (APP) production [29], improving tau protein phosphorylation [30], and reducing reactive oxygen species (ROS) generation [31], inhibiting the apoptotic and inflammatory signaling pathways [31,32], and increasing neurotransmitter expression [33]. This comprehensive review sheds light on the potential saponins as therapeutic agents for AD and related neurological disorders.

Figure 1. Representative triterpenoid saponins include (A) Oleanane, (B) Ursane, (C) Lupane, (D) Dammarane and steroidal saponins include (E) Cholestane, (F) Furostane, (G) Spirostane, (H) Cardenolide.

Aβ is a peptide that is a major component of the senile plaques found in the brains of people with AD [34]. Its accumulation is highly neurotoxic and is considered a hallmark of AD [35], which can result in impaired cognitive function, including spatial memory [36]. Aβ is generated from the APP and is typically enclosed by microglia and dystrophic synapses that aggregate around neurons [37,38]. APP is a transmembrane protein located in the synapse of neurons, which can be cleaved by both amyloid and nonamyloid pathways [39]. In the nonamyloid pathway, APP is sequentially cleaved by α-secretase (mainly ADAM10) and γ-secretase [40], resulting in P3 peptide (P3), C83 carboxy-terminal fragment (C83), APP intracellular domain (AICD), and soluble amyloid precursor protein-α (sAPPα) with beneficial neurotrophic effects [41]. Conversely, in the amyloid pathway, APP is first cleaved by β-secretase and sAPPβ is secreted [42]. Subsequently, γ-secretase cleaves the C-terminal fragment (C99) of the residual APP and eventually leads to the release of peptides of different lengths [43]. The most prevalent of them are Aβ1-40 and Aβ1-42 [44], which are neurotoxic fragments capable of oligomerization, aggregation, and subsequent plaque formation [45]. , Aβ is degraded by a variety of proteases, most notably insulin-degrading enzymes (IDE) and neprilysin (NEP) [46]. However, the production or activity of these clearance enzymes may decrease with age, leading to a failure to clear Aβ in a timely manner [47]. This phenomenon has been linked to the reduced activity of the peroxisome proliferator-activated receptor γ (PPARγ) [48], which is a transcription factor that regulates the expression of IDE and Bace1, reduces Aβ production [49], promotes Aβ clearance [50], and exerts neuroprotective effects [51]. An imbalance between Aβ production and clearance is responsible for the accumulation of Aβ in the brain [52]. In order to develop novel treatments for AD, it may be beneficial to inhibit Aβ production, enhance its clearance, or directly combat its neurotoxicity [53]

Natural saponins have shown potential in affecting Aβ metabolism through different pathways [54]. For example, some natural saponins are able to inhibit the formation of Aβ by reducing APP production. Ginsenoside Rg1, a tetracyclic triterpenoid saponin extracted from ginseng [55], has been shown to reduce Aβ deposition in APP/presenilin 1(PS1) double transgenic AD model mice by lowering APP levels [56]. Pharmacokinetic studies have also shown that ginsenoside Rg1 can cross the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCSFB), which provides theoretical support for its ability to improve learning and memory abilities [57]. Xanthoceraside, another tetracyclic triterpenoid saponin, extracted from the bark of the Xanthoceras sorbifolia Bunge commonly used in traditional Chinese medicine (TCM) to treat rheumatism [58]_, has been shown to reduce APP protein levels and Aβ deposition in the cerebral cortex and hippocampus, thereby ameliorating cognitive function dysfunction in an AD mouse model induced by Aβ intracerebroventricular (ICV) injection [59]. In addition, ginsenoside Rh2, another ginseng derivative used in TCM, has been reported to regulate APP expression by reducing cholesterol and lipid raft levels. This ultimately led to an increase in sAPPα levels and a decrease in Aβ concentrations [60].

Most saponins have been shown to inhibit Aβ deposition by modulating the activity of APP-processing enzymes, such as ginsenoside Rg1 [61], RAPO-1-3 [62], onjisaponin B [62], pseudoginsenoside-F11 (PF11) [63], theasaponin E1 [64], anginsenoside (20S)-Rg3 [65], and ginsenoside C-K (CK) [66]. Ginsenoside Rg1 reduces the γ-secretase responsible for Aβ production by attenuating the Aβ-mediated inhibition of cAMP response element-binding protein (CREB) phosphorylation and protein kinase A (PKA) activity [61]. It also upregulates ADAM10 while reducing BACE1 in Wistar rat models of AD induced by ovariectomy (OVX) and D-galactose (D-gal) [67]. In sAPPα-transfected HT22 cells and neuroblastoma (SH-SY5Y) cells, ginsenoside Rg1 has been found to increase the levels of sAPPα and estrogen receptor (ER) α, elevate α-secretase activity, and decrease extracellular release of Aβ. Further studies have shown that these effects are mediated by the upregulation of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and phosphorylated protein kinase B (pAkt) [68] but can be reversed by ER antagonists and potentially attenuated by inhibitors of protein kinase C (PKC), MAPK, and phosphatidyl 3-kinase (PI3K) [68]. Yuan Zhi (RAPO) is a TCM formulation that is commonly used to treat dementia due to its neuroprotective effects [69]. Its active ingredient, RAPO-1-3, and onjisaponin B, an acyl saponin with a similar constituent to RAPO-1-3, have been found to reduce Aβ production by promoting the degradation of APP protein through interference with the PS1/BACE1 interaction [62]. Another compound, PF11, which is a pentacyclic triterpene abundant in ginseng [70], has also demonstrated efficacy in inhibiting APP amyloidogenic processing. By reducing the expression of BACE1, PF11 reduced Aβ deposition and ameliorated cognitive impairment and synaptic dysfunction in SAMP8 mice [63]. Theasaponin E1, a pentacyclic triterpene extracted from green tea seeds [71], has been shown to reduce the production of Aβ by increasing the activity of NEP and ADAM10 in APP (SweAPP N2a) cells while inhibiting the expression of BACE1, APP, and PS1 [64]. Furthermore, CK, which is produced through the degradation of protopanaxadiol saponins by the gut microbiota [72], has been studied for its neuroprotective properties. Currently, it is primarily obtained by glycosyl hydrolysis of proto-ginsenoside diol-type saponins [73]. In scopolamine-induced ICR mice, CK was found to reduce the expression of BACE1 and PS1, increase IDE activity, reduce Aβ expression, and improve memory function [66]. In addition, ginsenoside (20S)-Rg3, a component of heat-processed ginseng, has been found to reduce Aβ levels by increasing phosphatidylinositol 4-kinase IIα(PI4KIIα) activity and ultimately decrease the expression of γ-secretase by decreasing the association of PS1 fragments and lipid rafts in cultured primary neurons and in the brains of an AD mouse model [65].

Aside from inhibiting Aβ production, certain saponins have been found to promote the clearance of Aβ. For example, minor ginsenoside F1, a trace ginsenoside derived from Panax ginseng [74], has been shown to effectively reduce Aβ plaques and alleviate cognitive impairment in APP/PS1 mice by enhancing the expression of pCREB [75]. Similarly, Bacopaside I (BS-I), a tetracyclic triterpene and standardized extract of Bacopa monnieri [76], has been shown to be neuroprotective and improve cognitive function [77]. The aglycones of Bacopa monnieri and its derivatives have good intestinal absorption and BBB permeability [78]. Recent studies suggest that BS-I induces sufficient innate immune stimulation and phagocytosis to promote amyloid clearance, thereby reducing amyloid plaque burden in APP/PS1 mice [79]. In addition, Aβ deposition in the brain is linked to the dysfunction of the endosomal–lysosomal system dysfunction [80], which is regulated by the transcription factor EB (TFEB) [81]. PF11 has been observed to increase Aβ clearance by promoting the mammalian target of rapamycin (mTOR)-dependent TFEB-mediated lysosome biogenesis and alleviating endosomal–lysosomal system dysfunction through the conversion of Rab5 to Rab7 [82].

2.2. Inhibiting Aberrant Tau Protein Phosphorylation

2.3. Anti-Inflammatory Effect