Research Progress on Natural Plant Molecules in Regulating the Blood-Brain Barrier in Alzheimer's Disease

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.

Keywords: Alzheimer’s disease; blood–brain barrier; mechanisms; natural plant molecules; research progress; treatment.

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.

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.

Figure 5

Chemical structure of these natural plant molecules.