Yuqian An

Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder with abnormal accumulation of amyloid-β (Aβ) plaques, neuroinflammation and impaired neurogenesis. Mounting evidences suggest that single-target drugs have limited effects on clinical treatment and alternative or multiple targets are required. In recent decades, natural compounds and their derivatives have gained increasing attention in AD drug discovery due to their inherently enormous chemical and structural diversity. In this study, we demonstrated that naringin dihydrochalcone (NDC), a widely used dietary sweetener with strong antioxidant activity, improved the cognitive function of transgenic AD mice. Pathologically, NDC attenuated Aβ deposition in AD mouse brain. Furthermore, NDC reduced periplaque activated microglia and astrocytes, indicating the inhibition of neuroinflammation. It also enhanced neurogenesis as investigated by BrdU/NeuN double labeling. Additionally, the inhibition of Aβ level and neuroinflammation by NDC treatment was also observed in an AD cell model or a microglia cell line. Taken together, our study indicated that NDC might be a potential therapeutic agent for the treatment of AD against multiple targets that include Aβ pathology, neuroinflammation and neurogenesis.

Microglia play important roles in maintenance of brain homeostasis, while due to some pathological stimuli in aging‐related neurodegenerative diseases including Alzheimer’s disease, they are malfunctioning. Here, we demonstrated that amyloid‐ β (A β ) accelerated cell senescence characterized by the upregulation of p21 and PAI‐1 as well as senescence‐associated beta‐galactosidase (SA‐ β ‐gal) in human microglial cells. Consistently, A β induced the senescence‐associated mitochondrial dysfunctions such as repression of ATP production, oxygen consumption rate (OCR), and mitochondrial membrane potential and enhancement of ROS production. Furthermore, A β was found to significantly suppress mRNA expression and protein level of Sirtuin‐1 (SIRT1), a key regulator of senescence, and inhibit mRNA expression and translocation of NRF2, a critical transcription factor in inflammatory responses, leading to impairment of phagocytosis. Rescue of SIRT1, as expected, could counteract the pathological effects of A β . In summary, our findings revealed that A β accelerates human microglial senescence mainly through its suppression of the SIRT1/NRF2 pathway and suggested that genetic and pharmaceutical rescue of SIRT1 may provide a potential alternative treatment.

Neuroinflammation induced by over-activated glia cells is believed to be a major hallmark of Alzheimer’s disease (AD) and a hopeful target against AD. A rhamnoside PL201 was previously reported to promote neurogenesis and ameliorate AD pathologies, and in this study we revealed that PL201 also significantly reduced accumulation of the activated microglia and pro-inflammatory cytokines in APP/PS1 mice. In vitro, PL201 consistently suppressed the microglia induction of pro-inflammatory cytokines after stimulation with lipopolysaccharides and Aβ42. Further mechanistic studies demonstrated that PL201 considerably enhanced the expression level and the nuclear translocation of Nrf2, a key regulator of neuroinflammation. Moreover, PL201 effectively stimulated Nrf2 signaling cascade, including up-regulation of HO-1 and down-regulation of NF-κB pathway. Thus, our findings indicated the anti-neuroinflammatory effect by PL201 in vivo and suggested PL201 or the alike with multiple functions such as neurogenesis, mitochondria maintenance, and anti-neuroinflammation, could be a promising candidate in AD treatment.