Artemisia annua Extract Improves the Cognitive Deficits and Reverses the Pathological Changes of Alzheimer’s Disease via Regulating YAP Signaling

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the occurrence of cognitive deficits. With no effective treatments available, the search for new effective therapies has become a major focus of interest. In the present study, we describe the potential therapeutic effect of Artemisia annua (A. annua) extract on AD. Nine-month-old female 3xTg AD mice were treated with A. annua extract for three months via oral administration. Animals assigned to WT and model groups were administrated with an equal volume of water for the same period. Treated AD mice significantly improved the cognitive deficits and exhibited reduced Aβ accumulation, hyper-phosphorylation of tau, inflammatory factor release and apoptosis when compared with untreated AD mice. Moreover, A. annua extract promoted the survival and proliferation of neural progenitor cells (NPS) and increased the expression of synaptic proteins. Further assessment of the implicated mechanisms revealed that A. annua extract regulates the YAP signaling pathway in 3xTg AD mice. Further studies comprised the incubation of PC12 cells with Aβ1–42 at a concentration of 8 μM with or without different concentrations of A. annua extract for 24 h. Obtained ROS levels, mitochondrial membrane potential, caspase-3 activity, neuronal cell apoptosis and assessment of the signaling pathways involved was performed using western blot and immunofluorescence staining. The obtained results showed that A. annua extract significantly reversed the Aβ1–42-induced increase in ROS levels, caspase-3 activity and neuronal cell apoptosis in vitro. Moreover, either inhibition of the YAP signaling pathway, using a specific inhibitor or CRISPR cas9 knockout of YAP gene, reduced the neuroprotective effect of the A. annua extract. These findings suggest that A. annua extract may be a new multi-target anti-AD drug with potential use in the prevention and treatment of AD.

Another Use for a Proven Drug: Experimental Evidence for the Potential of Artemisinin and Its Derivatives to Treat Alzheimer’s Disease

“…In a very similar fashion, Artemisia annua extract was recently shown to attenuate neuroinflammation in the brain of 12-month-old female 3xTg mice after 3 months of treatment. GFAP and Iba-1 (a microglia marker) expressions, as well as levels of IL-6, TNF-α, and IL-1β, were significantly reduced in the hippocampus and cortex of the mice treated with either 6.7 mg/mL or 20 mg/mL, in parallel exhibiting lower Aβ accumulation, tau hyperphosphorylation, and milder cognitive deficits [85]. These results are supported by findings in nontransgenic mouse AD models.…”

“…Additionally, significant reductions in the phosphorylated tau (Ser396 and Thr212) levels but not in total tau levels were recorded in the brains of artemisinin-treated mice when compared to control 3xTg mice [84]. These results were confirmed by a recently published study using Artemisia annua extracts in different concentration rather than isolated artemisinins [85]. In this study, the oral administration of the extract (6.7 mg/mL vs. 20 mg/mL) to 9-month-old female 3xTg AD mice for 3 months reduced both Aβ accumulation and tau hyper-phosphorylation (Thr181) to within a comparable range in the cortex and hippocampus.…”

“…The effect of extract on Aβ deposition and APP and Aβ 1-42 levels in brain homogenates was higher in animals treated with lower concentrations of the extract since mice receiving the dosage of 20 mg/mL exhibited a more prominent reduction in tau-phosphorylation compared to animals treated with 6.7 mg/mL. The plant extract did not affect the expression of total tau, altogether indicating an eventual direct effect of the artemisinin extract on tau pathology [85].…”

“…More recently, an artemisia extract was reported to rescue neuronal cell apoptosis in 9-month-old 3xTg AD mice accompanied by changes in the expressions of different apoptosis regulators. In addition to the emodulation of Bax, Bcl-2 and cleaved caspase 3 levels, artemisinin extract treatment activated YAP/TEAD2/Survivin signaling, promoting a significant increase in anti-apoptotic Survivin protein levels, while significantly reducing the level of pro-apoptotic promyelocytic leukemia protein [85]. YAP (Yes-associated protein) is a transcriptional cofactor that regulates cell death and survival by binding to different transcription factors such as p73 and TEAD (TEA-domain family member) and seems to be a key player in the molecular network of AD [119].…”

“…Moreover, fewer data are available concerning the effects of artemisinins on excitatory synapses. Zhou et al reported that Artemisia annua extract (6.7 mg/mL and 20 mg/mL) elevated the expression levels of synaptophysin, a protein found in presynaptic terminals, and PSD95, a key postsynaptic protein of excitatory synapses, above wild-type levels in the brains of 9-month-old 3xTg AD mice [85]. In our own studies, a significant increase in the PSD95 mRNA level was measured in APP/PS1 mice brains upon treatment with 100 mg/kg artesunate compared to the control APP/PS1 mice [77].…”