Ginsenosides are the most important pharmacological active ingredient of ginseng, with multiple biological therapeutic targets, mild action and no side effects.

 It is having shown beneficial effects in vitro and in vivo models of AD. 

In this review, we analyze large literature, summarize the inhibition of ginsenosides fibrous extracellular deposition of β-amyloid (Aβ) and neurofibrillary tangles (NFTs) of possible mechanisms, and explain the effects of ginsenosides on AD neuroprotection from the aspects of antioxidant, anti-inflammatory, and anti-apoptosis, prove the potential of ginsenosides as a new class of drugs for the treatment of AD. 

In addition, according to the current clinical application status of natural drugs, this paper analysis the delivery route and delivery mode of ginsenosides from the perspective of pharmacokinetics, providing a deeper insight into the clinical application of ginsenosides in the treatment of AD.

Introduction

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease, namely the gradual loss of neuronal structure and function in the brain, characterized by memory loss, cognitive and functional deficits, and behavioral disorders. At present, no effective clinical drugs have been found to prevent the progression of the disease. 

Though the pathogenesis of the disease is not fully understood, its major pathological features have been identified: extracellular β-amyloid (Aβ) formation and aggregates of the phosphorylated microtubule-associated protein Tau in neurofibrillary tangles (NFTs) (Lane et al., 2018) (Figure 1). More and more evidence suggests that Aβ and tau proteins begin to accumulate years before clinical symptoms appear (Bejanin et al., 2017). According to the amyloid cascade hypothesis, it is the main influencing factor that the accumulation of Aβ in the brain drives the pathogenesis of AD. 

Continuous aggregation and deposition of Aβ peptides induce inflammation and microglial cascades, broad-spectrum ion and neurotransmitter abnormalities, mitochondrial dysfunction, oxidative stress, etc. The imbalance of Aβ production and clearance leads to the hyperphosphorylation of tau to NFTs, which further leads to synaptic and neuronal dysfunction and destruction, ultimately leading to extensive cortical dysfunction (Atri, 2019). 

In addition to the Aβ hypothesis, the cholinergic hypothesis has a place in the development of potential therapies for AD. The hypothesis suggests that cholinergic deficits are thought to be responsible for the cognitive, behavioral, and overall functional characteristics of AD. At present, the treatment of neurological diseases is mainly drug and surgical treatment. 

Current treatment methods mainly use acetylcholinesterase (AChE) inhibitors, such as Donepezil, Rivastigmine hydrogen tartrate, Galanthamine, etc. (Lane et al., 2018), to enhance cholinergic neurotransmission by preventing the hydrolysis of acetylcholine and subsequently increasing its synaptic level. 

but, the effect is not significant, and long-term use of drugs can lead to drug accumulation and poisoning, resulting in certain side effects, such as vomiting, diarrhea and other gastrointestinal reactions (Vaz and Silvestre, 2020). It is worth noting that these drugs can only improve some of the main symptoms of AD, but do not delay or reverse the onset of AD. On the other hand, surgical treatment often increases the chance of infection and other dysfunction.