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16 November 2023

Research Progress on Natural Plant Molecules in Regulating the Blood–Brain Barrier in Alzheimer’s Disease

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1
Basic Theory of Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin 150040, China
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Department of Chinese Pharmacology, Heilongjiang University of Chinese Medicine, Harbin 150040, China
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Science and Education Section, Zhangjiakou First Hospital, Zhangjiakou 075041, China
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Department of Internal Medicine, Heilongjiang University of Chinese Medicine, Harbin 150040, China
Molecules2023, 28(22), 7631;https://doi.org/10.3390/molecules28227631
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Abstract

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder. With the aging population and the continuous development of risk factors associated with AD, it will impose a significant burden on individuals, families, and society. Currently, commonly used therapeutic drugs such as Cholinesterase inhibitors, N-methyl-D-aspartate antagonists, and multiple AD pathology removal drugs have been shown to have beneficial effects on certain pathological conditions of AD. However, their clinical efficacy is minimal and they are associated with certain adverse reactions. Furthermore, the underlying pathological mechanism of AD remains unclear, posing a challenge for drug development. In contrast, natural plant molecules, widely available, offer multiple targeting pathways and demonstrate inherent advantages in modifying the typical pathologic features of AD by influencing the blood–brain barrier (BBB). We provide a comprehensive review of recent in vivo and in vitro studies on natural plant molecules that impact the BBB in the treatment of AD. Additionally, we analyze their specific mechanisms to offer novel insights for the development of safe and effective targeted drugs as well as guidance for experimental research and the clinical application of drugs for the prevention and treatment of AD.

1. Introduction

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by progressive and insidious development, leading to behavioral and cognitive dysfunction. The aging global population and the associated risk factors have contributed to an alarming increase in the number of individuals affected by AD, with projections estimating over 150 million cases worldwide by 2050. This escalating prevalence poses a significant global health challenge, impacting both individuals and society [1,2,3]. Consequently, there is a pressing need to identify safe and effective preventive and control measures.
The pathogenesis of AD remains incompletely understood, primarily due to the intricate interplay between genetic and environmental factors, as well as the diverse biological pathways involved in disease onset and progression. However, certain neuropathological features of AD, such as amyloid plaques and neurofibrillary tangles (NFTs), have been consistently observed. Moreover, emerging evidence suggests that disruption of the blood–brain barrier (BBB) plays a crucial role in AD. BBB breakdown allows neurotoxic blood-derived products, cells, and pathogens to infiltrate the brain, triggering inflammatory and immune responses that impair neuronal and microvascular function. These processes can initiate neurodegenerative pathologies through various pathways. The BBB also restricts the entry of drugs into the brain, posing challenges for targeted drug delivery to the brain. This limitation hinders the development of therapeutic drugs [4,5]. Currently, the US FDA has only approved cholinesterase inhibitors and N-methyl-d-aspartate antagonists for the treatment of AD, despite their high incidence of adverse drug reactions. These drugs also have limitations in terms of cost and tolerance. Meanwhile, other drugs with targeted mechanisms are either undergoing clinical trials or have failed to enter the market [6,7,8]. So far, many therapeutic strategies in modern medicine have been unsuccessful in intervening in the disease process and have only been able to manage symptoms [4]. Therefore, the search for a safe and effective drug-targeting pathway and the development of multifunctional and multitargeted drugs for the progression of AD within the complex biological pathways is both challenging and promising.
In recent years, as research on the mechanism of natural plant molecular therapy for AD has advanced, its unique therapeutic advantages have become increasingly apparent. For instance, these molecules can specifically target the brain and possess characteristics such as being multi-targeting, multi-channeling, and having minimal side effects. Specifically, certain monomers and components of traditional Chinese medicine can be combined to offer personalized and precise treatment strategies. However, the specific role of natural plant molecules in regulating the BBB, with their complex pathways and mechanisms of action, has not been clearly explained. This paper aims to comprehensively explore the role of natural plant molecules in regulating the BBB of AD. It will achieve this by systematically reviewing the structure and function of the BBB, the relationship between the BBB and the pathological aspects of AD, the specific mechanisms through which the BBB influences the progression of AD, and the pathways by which natural plant molecules regulate the BBB in AD. The findings will contribute to the identification of a new therapeutic target for the prevention and treatment of AD, and will also serve as a valuable reference for future experimental research and clinical applications.

2. Structure and Function of the Blood–Brain Barrier

The BBB serves as a dynamic interface between the peripheral circulation and the central nervous system (CNS). It primarily consists of brain capillary endothelial cells, which are surrounded by the basement membrane (BM), pericytes, and astrocytes in the neurovascular unit (NVU). Some studies also consider the NVU as a fundamental component of the BBB (Figure 1) [9,10]. The BBB plays a crucial role in regulating molecular exchanges between blood flow and the brain parenchyma, thereby maintaining CNS homeostasis [11].
Figure 1. The physiological structure of the blood–brain barrier: (A) Cross-sectional structure of the blood–brain barrier; (B) Continuity plane structure of blood–brain barrier.

2.1. Endothelial Cell

Brain microvascular endothelial cells (BMECs) are responsible for maintaining the structural and functional integrity of the BBB. This is achieved through the presence of tight junctions (TJs) and adherens junctions (Figure 1A), which create distinct luminal (apical) and basolateral compartments [12]. The TJ complexes between CNS endothelial cells form a paracellular diffusion barrier for small hydrophilic molecules and ions [13,14,15]. Additionally, the high transendothelial resistance limits the passage of transcellular vesicles through the vessel wall [16]. The influx and efflux of specific substrate macromolecules and proteins within the brain are regulated by passive and active receptors/channels in the lumen or on the lumen surface (Figure 1B) [17,18,19]. As a communication interface between the CNS and the peripheral nervous system, BMECs play a crucial role in regulating circulation, immunity, and controlling the entry of cells and other substances into the brain microenvironment [20].

2.2. Astrocytes

Astrocytes, a type of astrocytic glial cells distributed throughout the CNS, play a crucial role in maintaining brain homeostasis and neurological function [21]. They have the ability to chemically and physically interact with neuronal synapses and cerebral microvasculature (Figure 1B). There are several key functions of astrocytes. Firstly, they maintain and regulate the BBB, which is achieved by upregulating the expression of transporter proteins, polarized localization, and specialized enzyme systems, thus promoting TJ stability [22]. Secondly, astrocytes act as critical regulators of the immune response in the CNS. They are involved in phagocytosis, antigen presentation, and the transportation of immune cells [23,24,25]. These functions can either promote or inhibit neuronal damage and inflammation. Additionally, astrocytes interact with microglia to coordinate defense responses [26]. Thirdly, astrocytes can protect neurons by secreting brain-derived neurotrophic factor (BDNF), glial-cell-derived neurotrophic factor (GDNF), and various antioxidants [27]. Fourthly, astrocytes are also involved in neurotransmission. They regulate astrocyte excitability through the activation of cell surface receptors and transporter proteins (Figure 1B). This leads to dynamic changes in intracellular calcium (Ca2+) or sodium (Na+), as well as changes in ionic and electrical properties of astrocytes. These changes have significant non-autonomous effects on brain function, including the regulation of synaptic activity, neuronal metabolism, and regional blood supply [28]. Finally, astrocyte-derived, wingless-related integration sites (Wnts) play a crucial role in maintaining the activity of Wnt/β-catenin in both endothelial cells and astrocytes. This, in turn, controls the expression of Cav-1, regulates vesicle abundance, and ensures the integrity of terminal feet in the NVU. These processes are essential for maintaining the proper functioning of the endothelial BBB on neurons [29]. Additionally, astrocytes near cerebral microvessels are abundant in aquaporin-4 (AQP4), which is responsible for the uptake and degradation of amyloid β-protein (Aβ) [30,31].

2.3. Pericyte

Pericytes are parietal cells that line the septum of the capillary wall [32]. They are recruited by endothelial cells in new microvessels through signal transduction between platelet-derived growth factor-BB (PDGF-BB) and its pericyte receptor PDGFRβ [33,34]. Pericytes are embedded in the BM and attach to the surface of endothelial cells (Figure 1A), including capillaries, small precapillary arterioles, and small postcapillary veins [35,36]. Their high coverage in neural tissue determines their central role in the NVU (Figure 1) [37,38,39,40,41]. Pericytes interact with various components of the NVU, promoting the development of the BBB by supporting the germination, differentiation, and maturation of endothelial cells. This interaction induces the formation of TJs and pericytes also contribute to the construction of part of the BM (Figure 1B). In summary, pericytes play a crucial role in the development and maintenance of the BBB. Under inflammatory conditions, pericytes stimulate immune cells to produce cytokines and present antigens, which inhibits the infiltration of immune system cells into the CNS. Pericytes also guide the astrocyte end foot process towards the endothelial tube, initiate its polarization, and support proper neuronal function [42,43,44]. Additionally, pericytes regulate cerebral blood flow, promote vascular stability, and remove toxic cell by-products from the CNS [45,46].

2.4. Basement Membrane

The BM, a distinct type of extracellular matrix (ECM), is primarily located beneath endothelial and epithelial cells in the brain, with pericytes acting as the separating barrier (Figure 1A) [47,48]. The BM serves various functions, including providing structural support, anchoring cells, and facilitating signal transduction [49,50,51]. These components primarily consist of type IV collagen, laminin, nidogen, perlecan, and other structural proteins. BMECs, pericytes, and astrocytes on the BBB primarily synthesize these ECM proteins [52,53]. These ECM structural proteins form the fundamental physical framework that supports TJ assembly in cells [54]. Signal transduction between the BM and its associated cells primarily relies on two types of matrix transmembrane receptors: dystroglycan and integrins. It is also closely associated with extracellular ligands of the ECM [50]. The binding of these receptors or ligands can activate multiple growth factors and signaling cascades, regulating cell growth, differentiation, migration, and survival during the development and maintenance of the BBB. During cerebrovascular formation, angiogenic endothelial cells (ECs) express α4β1 and α5β1 integrins, which bind to the ECM ligand fibronectin and induce cell proliferation through MAPK (Mitogen-activated protein kinase) signal transduction [55,56].
In summary, the BBB consists of four primary physiological barrier functions. The first function is the physical barrier, which is formed by TJs between adjacent endothelial cells. This physical barrier is characterized by the absence of intercellular clefts and low pinocytosis activity, effectively preventing the passive absorption of endogenous and exogenous compounds by the brain. The second barrier function is the biochemical barrier, which is formed by numerous inflow and outflow transporters located on the lumen and adventitia of endothelial cells [12,57]. These transporters tightly regulate the entry and exit of substances into the brain, actively limiting the brain’s absorption of foreign organisms and regulating nutrient supply. The third barrier function is the metabolic barrier, which is formed by a variety of metabolic enzymes present in endothelial cells [58]. This barrier function is responsible for the degradation of neurotoxins, drugs, and other compounds. The fourth barrier function is the immune barrier, which is composed of BMECs and regulated by astrocytes. This barrier function restricts the entry of immune cells from the periphery into the brain.

3. The Relationship between the Blood–Brain Barrier and AD Pathology

Dysfunction of the BBB/NVU can be observed in three main pathological aspects: (1) Leakage of circulating substances from plasma to the CNS; (2) Dysregulation of transporters leading to inadequate nutrient supply, accumulation of toxins in the CNS, or entry of other compounds into the brain; (3) Abnormal expression or secretion of cell proteins in the BBB/NVU, which promotes inflammation, oxidative stress, and neuronal damage [59]. Current evidence [60,61,62] indicates that dysfunctional BBB/NVU cells contribute to the development of various CNS disorders, including AD, which is characterized by neurodegeneration and cognitive decline.
The pathogenesis of AD is associated with structural changes and dysfunctions of the BBB. These dysfunctions include reduced endothelial transport, loss of TJ integrity, and degeneration of pericytes and astrocytes, which can lead to increased BBB permeability, microhemorrhages, impaired glucose transport, impaired P-glycoprotein function, perivascular deposition of blood-borne products, disruption of ionic homeostasis, altered signaling, and immune infiltration (Figure 2 and Figure 3). These changes ultimately result in neuronal dysfunction and neurodegeneration [5,12,60]. Additionally, BBB dysfunction triggers neuroinflammation and oxidative stress, which enhance the activity of β-amyloid precursor protein-cleaving enzyme 1 (BACE1) and γ-amyloid precursor protein-cleaving enzyme, ultimately promoting the production of Aβ (Figure 2 and Figure 4) [63]. At the same time, the decrease in the level of low-density lipoprotein receptor-related protein 1 (LRP-1) and the increase in the level of the receptor for advanced glycation endproducts (RAGE) in the BBB impairs the transport of Aβ from the brain to the peripheral circulation, leading to its accumulation in the brain. LRP-1, a member of the low-density lipoprotein (LDL) receptor family, functions as a versatile scavenger and cargo transporter with signal transduction activity [64]. RAGE, a receptor for advanced glycation end products, is a multiligand receptor of the immunoglobulin superfamily located on the cell surface. RAGE expressed on the luminal side of the BBB facilitates the transport of Aβ from the blood to the brain. The progressive accumulation of Aβ in the brain, along with BBB dysfunction, can create a feedback loop that contributes to cognitive impairment and dementia (Figure 2 and Figure 4) [9]. Furthermore, BBB dysfunction interacts with tau pathology by inducing hyperphosphorylation of the tau protein, leading to the formation of NFTs. Additionally, certain tau proteins can cross the BBB in both directions, exacerbating tau pathology and contributing to BBB damage (Figure 2 and Figure 4) [9,65,66,67,68].
Figure 2. The connection between Alzheimer’s disease pathology and blood–brain barrier damage. The pathology of Alzheimer’s disease is closely related to the disruption of the blood–brain barrier; Aβ deposition and neurofibrillary tangles, as key pathological participants, interact with the blood–brain barrier. Firstly, under AD pathology, Aβ plaque deposition is caused by the gradual accumulation of Aβ monomers formed by the cleavage of APP (Aβ Oligomers, Aβ Fibrils, Diffuse Aβ Plaques), and NFTs are formed by the increased dissociation and hyperphosphorylation of tau proteins in the unstable microtubule system (p-tau, tau oligomers, paired helical filaments). Subsequently, Aβ and NFTs affect the blood–brain barrier, causing structural and functional disorders of the blood–brain barrier, leading to the following: (A) Ion steady-state destruction; (B) Astrogliosis and microgliosis; (C) Autophagy; (D) Cerebral amyloid angiopathy; (E) Cerebral microhemorrhages; (F) Transport disorders; (G): Toxic product deposition; (I) Synaptic connection damage. Conversely, related damage to the blood–brain barrier also promotes the formation of Aβ and NFTs. Finally, they jointly promote the pathological development of AD in this cycle.
Figure 3. The specific manifestations of BBB in the AD process. The changes in the main components of the blood–brain barrier are closely associated with the progression of Alzheimer’s disease (AD). Dysregulation of endothelial cell transport proteins, activation of astrocytes and microglia promoting neuroinflammation, as well as oxidative stress reactions lead to decreased coverage of pericytes and subsequent receptor shedding, alterations in the glycocalyx and basement membrane, decreased neuronal cell adhesion, decreased tight junction proteins, increased blood–brain barrier permeability, and increased protein extravasation. All of these are specific pathological manifestations of the blood–brain barrier during the progression of AD. CLDN, claudin; ZO, zona occludens; ICAM, intracellular adhesion molecules; CSF, cerebral spinal fluid; P-gp, P-glycoprotein; Glut1, glucose transporter 1; ↓:downregulation or inhibition; ↓↓: more severe downregulation; ↑: upregulation or activation; ↑↑: more severe activation.
Figure 4. Signaling pathways associated with BBB disruption in AD. BBB disruption in AD leads to dysregulation of multiple signaling pathways. These dysregulated pathways include the inflammatory response, oxidative stress, neurotransmitter imbalance, and cellular apoptosis. The dysregulation of these signaling pathways may contribute to neuronal damage and cognitive decline.
The accumulation of Aβ and tau in the brain is widely recognized as a typical pathological marker of AD. Their interaction with the BBB leads to various pathological changes, which can be categorized into the following eight parts: (1) Dysregulation of calcium ions in neurons and astrocytes leads to excitotoxicity and astrocytosis (Figure 2A) [69]. (2) The increase in reactive astrocytes and microglia affects synaptic transmission (Figure 2B) [70,71]. (3) The decrease in lysosomal degradation ability of neurons leads to autophagy and neuronal loss (Figure 2C) [72]. (4) The accumulation of Aβ in cerebral vessels promotes the development of cerebral amyloid angiopathy (CAA). This process also results in the rupture of the vascular wall, leading to cerebral microbleeds (Figure 2E), infarction, white matter lesions, and ultimately the destruction of synapses and neurovascular networks [73]. (5) CAA causes neurovascular dysfunction (Figure 2D), which further impairs the cognitive function of AD patients [74,75]. (6) Myelin breakdown affects synaptic connections in AD (Figure 2I) [76]. (7) The detachment or inactivation of receptor and enzyme-active substances leads to the failure of signal transduction and substance transport (Figure 2F). (8) The deposition of blood-derived products and neurotoxic substances leads to neuronal degeneration (Figure 2G).

4. The Specific Mechanism of BBB Affecting AD Progression

4.1. Endothelial Cells and Tight Junction Damage

In AD, the accumulation of Aβ leads to structural changes in BMECs, resulting in the disruption of cell-to-cell connections and impairing their interaction with other elements of the NVU. This directly affects the permeability of the BBB [77,78]. Additionally, the expression of TJ proteins, such as zonula occludens protein 1 (ZO-1), occludin, and claudin-1, -3, and -5, is decreased. Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) shedding and endothelial cell apoptosis also occur (Figure 3) [79,80,81]. The disruption and remodeling of TJ expose various mechanisms of BMEC injury. For example, Aβ induces the activation of the Ca2+/calmodulin-activated phosphatase calcineurin, leading to cytotoxic effects. Inflammatory mediators, including cytokines (e.g., IL-1β, IL-6, TNF-α, IL-12, and IL-23), chemokines (e.g., CCL2, CCL4, CCL3, CCL7, and CXCL10), complement components (e.g., C1q and C3), adhesion molecules (e.g., intercellular adhesion molecule (ICAM), p-selectin, and e-selectin), and matrix metalloproteinases (MMPs) of TJs, are activated in BMECs (Figure 3).
Simultaneously, leukocytes, microglia, and perivascular macrophages are collectively attracted to the perivascular region, along with mitochondrial damage and an increase in reactive oxygen species, such as NADPH (nicotinamide adenine dinucleotide phosphate) oxidase-2. These mechanisms described above contribute to the toxicity of endothelial Aβ and play a role in the inflammatory response of BMECs to TJ remodeling [82,83,84,85]. Additionally, endothelial cells enhance the transcellular transport of blood-derived substances through processes such as large protein endocytosis, gelatinase-dependent endocytosis, and gap-mediated transcytosis or vesicle transport [86,87,88,89]. The augmentation of paracellular and transcellular pathways results in the leakage of the NVU in AD. Despite limited evidence regarding histone modification, DNA methylation, and histone deacetylase activity in BMECs, recent studies [90,91] have demonstrated that dysregulation of microRNAs and long non-coding RNAs disrupts the integrity of the BBB. Specifically, the dysregulation of miR124, miR-107, and LINC00662 alters the transcription of ZO-1, claudin-5, and occludin in BMECs of AD patients through the modification of members belonging to the erythroid transformation-specific (ETS) transcription factor family and ETS-related genes [92].

4.2. Changes in Astrocyte Function and Structure

An increase in pathologic Aβ leads to functional and morphological changes in glial cells, particularly astrocytes and microglia, which are key cells involved in the inflammatory and immune response in the CNS. Aβ activates various receptors in astrocytes, with RAGE being the primary receptor that triggers the inflammatory pathway nuclear factor kappaB (NF-κB). This pathway is responsible for the transcription of numerous pro-inflammatory cytokines and chemokines in astrocytes, playing a crucial role in both pro-inflammatory (neurotoxicity) and immune regulation (neuroprotection) [93]. Additionally, NF-κB regulates other functions, including neuronal development, differentiation, apoptosis, neurite growth, and synaptic remodeling, all of which are dysregulated in AD [94]. Astrocytes produce cytokines such as TNF-α, IL-1β, IFN-γ, L-6, and TGF-β (Figure 3), which can enhance the activity of β- and γ-secretase enzymes through the c-Jun N-terminal kinase (JNK)-dependent MAPK pathway. This pathway cleaves APP and initiates Aβ formation [95].
Moreover, inflammatory mediators such as bradykinin can elevate intracellular calcium ion levels (Figure 3) through nicotinic receptors and the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) pathway in astrocytes (Figure 4) [96]. Simultaneously, the interaction between Aβ and multiple receptors and neurotransmitters in astrocytic calcium ion dysregulation can account for neurotoxicity and neurodegeneration [94]. Astrocytic metabolic dysfunction may contribute to cognitive impairment in AD through the disruption of the glutamate and gamma-aminobutyric acid (GABA) glutamine cycle [97,98,99]. Parameshwaran et al. [100] demonstrated the involvement of N-methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in the pathophysiology of AD. Additionally, dysfunction of NMDA receptors in astrocytes induced by Aβ can disrupt neuron–glial signaling [101]. Overall, dysfunction in glutamatergic signaling and excitatory toxicity can impact cognition. Oxidative stress in AD is strongly associated with mitochondrial dysfunction. The elevated levels of reactive oxygen species (ROS) and RNS result in the excessive production of superoxide (Figure 3), ultimately causing synaptic damage [102,103,104,105].
Aβ1-42 oligomers bind to RAGE on astrocytes, activating the NADPH oxidase (NOX) complex and leading to the production of ROS [106]. In addition, astrocytes can independently activate the extracellular signal-regulated kinase 1/2 (ERK 1/2) pathway and phosphorylate cytoplasmic phospholipase A2, resulting in mitochondrial dysfunction through the reduction of mitochondrial membrane potential, increased NOX activity, and excessive production of ROS [107]. Astrocytes express and secrete multiple MMPs, such as MMP-2 and MMP-9, which are capable of degrading both monomeric and fibroblastic forms of Aβ [101]. Structural changes in astrocytes result in the degeneration and disintegration of their protrusions, characterized by bead-like formations. These changes are accompanied by cytoplasmic vacuolization, atrophy, and swelling of astrocyte end pods [108,109]. At the end foot, the reduced levels of anchoring proteins, including AQP4, inward rectifier potassium channel (Kir4.1), and dystrophin 1, contribute to the further restriction of astrocyte–endothelial connections (Figure 3) [109,110,111]. These structural changes diminish the anchoring of astrocytes in the NVU and impair the interaction between cerebral blood flow and neurovascular coupling [112].

4.3. Pericyte Degradation

Pericyte degradation also plays a crucial role in the development of AD, as it affects the permeability of the BBB [113,114]. The deposition of vascular amyloid fibrils leads to the atrophy and invasive degradation of pericytes, resulting in reduced pericyte coverage (Figure 3). The extensive shedding of cell surface receptors expressed by pericytes causes them to lose function, leading to chronic hypoxia and decreased cerebral capillary perfusion, cerebral blood flow, and neurovascular coupling. These factors ultimately impact the integrity of the BBB [114,115,116]. The disruption of pericyte and endothelial cell contacts destabilizes TJs, while bidirectional pericyte/endothelial cell inflammatory signaling can also affect the stability of the TJ complex. Notably, inflammatory vesicle-forming, pattern-recognition receptor NLRP3 (nucleotide-binding domain-like receptor protein 3) and IL-1β are examples of factors that influence pericytes during BBB disruption (Figure 3) [114]. Furthermore, lower levels of pericyte-specific soluble proteins are directly associated with insufficient episodic memory, semantic memory, perceptual speed, visuospatial ability, and overall cognitive scores in AD patients [117].

4.4. Basement Membrane Thickening and Extracellular Matrix Protein Disorders

Thickening of the BM and remodeling of the ECM are crucial in the alteration of the NVU in AD vasculopathy. Previous studies have demonstrated a close association between BM thickening, fragmentation, and the presence of collagen and aggrecan in AD [80,118,119,120]. Moreover, the pathological accumulation of collagen can disrupt BBB transport, impair the interaction between endothelial cells and pericytes, and induce endothelial cell hypoxia, ultimately compromising BBB integrity [120]. Recent clinical and experimental studies have revealed elevated levels of perlecan, agrin, and fibronectin, as well as reduced levels of laminin, at the BBB/NVU in AD patients. The increase in these proteins in the perivascular space and BM is associated with Aβ accumulation, inflammation, apoptosis, and angiogenesis [120,121]. Indirectly, perlecan and fibronectin impact BBB integrity by promoting the inflammatory process and influencing intercellular interactions [121]. Alterations in the structure and composition of the BM ECM protein may facilitate the migration of circulating leukocytes to the brain during inflammation [59]. Changes in the glycocalyx and BM (Figure 3) affect the cell adhesion of NVU in AD. Research has demonstrated that these alterations are attributed to elevated levels of proteoglycans within the brain. Notably, hyaluronic acid, a glycocalyx and capillary BM proteoglycan, exhibits increased levels in cerebrospinal fluid samples of individuals with AD [122,123]. The rise in HA protein levels correlates with heightened cognitive decline in patients with AD [124]. Collagen and aggregation proteins, acting as proteoglycans, are also implicated.

6. Discussion and Conclusions

Natural plant molecules have a wide range of sources, and the medicinal components mentioned in the above content are widely present in vegetables and fruits consumed in daily diets. However, they are most abundant in many plants and herbal medicines, and their extraction processes are more advanced. In particular, traditional Chinese herbal medicines, which are currently the focus of intense research, have great potential in terms of their active ingredients in modern studies. Thousands of years ago, the therapeutic effects of these natural products were already recognized through human medical experiences, which involved the use of animals and plants from nature for drug therapies and dietary treatments. Returning to the origins, our focus is now directed towards these animal and plant medicinal materials, particularly herbal plants. These materials are not only widely available but also rich in medicinal components. Some of them are even referred to as natural antioxidants, which serve as important sources for new drug development and as effective means for preventing and treating diseases. Recently, an increasing number of natural plant molecules have been discovered to have a significant impact on AD, with the key mechanism being closely associated with the regulation of the BBB.
Previous studies have clearly demonstrated a close relationship between the pathogenesis of AD and the BBB. Several studies indicate that age-related changes in the BBB may precede the onset of AD in the elderly population [254]. If this is the case, further emphasis can be placed on the prevention of AD in the elderly population. Despite the ample experimental support and extensive research on the underlying mechanisms, there is a scarcity of reports on drugs that directly target the BBB. The poor solubility and low bioavailability of these drugs make it challenging to penetrate the BBB. Consequently, in recent years, immunotherapy, gut microbiota intervention, and physical exercise have garnered attention [255]. However, the benefits they offer require a longer duration and patience. Therefore, Hao Z et al. [256] proposed alleviating AD through exercise targeting the brain–gut axis, as well as the prevention and treatment of AD through exercise combined with polyphenols. Currently, numerous studies have been conducted in the field of nanotechnology to achieve targeted drug delivery and enhance drug bioavailability, resulting in significant advancements in nanomedicine and intranasal administration [257,258]. However, breakthrough results are still lacking, and the focus of nanotechnology applications is gradually shifting towards natural molecules [259]. Despite the lack of separate reports on the regulatory effects of the aforementioned plant molecules on the BBB, our research on their treatment of AD has revealed their ability to regulate BBB-related pathways, suggesting their potential for AD treatment and prevention. Thus, investigating the regulation of BBB-related targets using natural plant molecules could offer a novel approach to intervene in AD progression and enhance cognitive function.
In conclusion, the regulatory mechanism of natural plant molecules on the BBB in AD is both extensive and complex. Nevertheless, there is no doubt that natural plant molecules possess strong targeting capabilities as drugs for AD treatment. They can effectively penetrate the BBB and offer inherent advantages in maintaining its integrity and regulating its function. They promote the transport of Aβ, reduce neurotoxicity, protect neurons from damage, and improve the pathological features of AD through anti-inflammatory, antioxidant, signal pathway regulation, and inhibition of cell apoptosis. These effects have been demonstrated in animal and cell experiments including the restoration of learning and memory abilities. However, there is currently no clear research on the toxic side effects associated with these plant molecules. Although these molecules are relatively reliable, it is still necessary to conduct toxicological experiments for detection. Subsequent clinical trials are needed to further confirm the multi-pathway targeting effect of natural plant molecules on the BBB in AD patients. Additionally, the combined effect of multiple molecules should be observed based on the research of individual plant molecules. Furthermore, general pharmacology, pharmacokinetics, and pharmacogenetics should study issues such as dosage form and metabolism time. This is a complex and challenging task that faces various problems, including trial design, trial period definition, ethical review, and technical funding support. Therefore, more effort is required to maximize the biological activity of these natural plant molecules on the AD BBB and develop more effective therapeutic drugs.

Author Contributions

Conceptualization, methodology, and writing—original draft preparation, W.W.; Software, J.H.; Investigation, P.H.; Resources, J.Z.; Data curation, Y.W.; Supervision and writing—review and editing, F.J.; Funding acquisition, writing—review and editing, Y.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (81774197), and the Natural Science Foundation of Heilongjiang Province (LH2023H057, LH2022H070).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

All data are available in the manuscript and they are shown in the figures and tables.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ADAlzheimer’s disease
AβAmyloid β-protein
NFTNeurofibrillary tangle
BBBBlood–brain barrier
NVUNeurovascular unit
CNSCentral nervous system
BMECsBrain microvascular endothelial cells
TJTight junction
BDNFBrain-derived neurotrophic factor
AQP4Aquaporin-4
PDGF-BBPlatelet-derived growth factor-BB
BMBasement membrane
ECMExtracellular matrix
MAPKMitogen-activated protein kinase
BACE1β-amyloid precursor protein cleaving enzyme 1
LRP-1Low-density lipoprotein-receptor-related protein 1
RAGEReceptor for advanced glycation endproducts
CAACerebral amyloid angiopathy
ZO-1Zonula occludens protein 1
PECAM-1/CD31Platelet endothelial cell adhesion molecule-1
ICAMIntercellular adhesion molecule
MMPsMatrix metalloproteinases
NADPHNicotinamide adenine dinucleotide phosphate
ETSErythroid transformation-specific
NF-κBNuclear factor kappaB
JNKc-Jun N-terminal kinase
PI3KPhosphoinositide 3-kinase
AktProtein kinase B
NMDAN-methyl-D-aspartic acid
AMPAAlpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
ROSReactive oxygen species
ERKExtracellular signal-regulated kinase
NOXNADPH oxidase
NLRP3N=Nucleotide-binding domain-like receptor protein 3
PPARγPeroxisome proliferator-activated receptor gamma
COX-2Cyclooxygenase-2
iNOSInducible nitric oxide synthase
GSK-3βGlycogen synthase kinase-3β
PTSPterostilbene
Bcl-2B-cell lymphoma-2
BaxBCL-2-associated X
MDAMalondialdehyde
SODSuperoxide dismutase
GSHGlutathione
cAMPCyclic adenosine monophosphate
CREBcAMP response element-binding protein
PSD95Postsynaptic density protein 95
PDE4Phosphodiesterase4
Nrf2Nuclear factor erythroid 2-related factor 2
AMPKAdenosine 5′-monophosphate (AMP)-activated protein kinase
Ht22Mouse hippocampal neuronal cells
GAGallic acid
ADAM10A disintegrin and metalloprotease 10
LTPLong-term potentiation
EGCGEpigallocatechin gallate
LPSLipopolysaccharide
TLR4Toll-like receptor 4
mTORMammalian target of rapamycin
LC3II microtubule-associated proteins light chain 3 II
PKAProtein kinase A
TrkBTropomyosin-related kinase B
AChEAcetylcholinesterase
Keap1Kelch-1ike ECH-associated protein l
GSSGGlutathione disulfide
BAIBaicalin
Cyt-CCytochrome-c
SalSalidroside
D-galD-galactosamine
SIRT1Sirtuin 1
NeuNNeuron-specific nuclear protein
EREndoplasmic reticulum
ICAIcariin
WntWingless-related integration site
PFCPrefrontal cortex
MAP2Microtubule-associated protein 2
PNTSPanax notoginseng Total Saponins
HO-1Heme oxygenase 1
AS-IVAstragaloside IV
SalASalvianic acid A

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