Naringin Dihydrochalcone Ameliorates Cognitive Deficits and Neuropathology in APP/PS1 Transgenic Mice.

Wenjuan Yang,Keyan Zhou,Yuqian An,Jing Lu,Yue Zhou,Gang Pei,Shichao Huang,Tingting Hu

doi:10.3389/fnagi.2018.00169

Abstract

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.

Highlights

Alzheimer’s disease (AD) is the most common type of dementia and has no effective cure so far
Multiple factors are involved in the pathogenesis of AD: (1) the accumulation of amyloid-β (Aβ) and excessive Aβ aggregation into plaques are considered the trigger of pathological events for AD (Holtzman et al, 2011); (2) neurofibrillary tangles composed of hyperphosphorylated tau protein contribute to neuronal dysfunction and involve in the progression of AD (Holtzman et al, 2011); (3) neuroinflammation is mediated by microglia and astrocytes and in response to brain damage (e.g., Aβ accumulation, neurofibrillary tangles), proinflammatory cytokines and mediators are produced, leading to chronic inflammation and neurodegeneration
We found that compared with wild type (WT) mice, APP/PS1 mice spent more time in locating the platform (p < 0.001), indicating it exhibited significant cognitive decline in learning, and there was no significant difference between naringin dihydrochalcone (NDC)-treated mice and WT mice (p > 0.05), indicating that the cognitive function of spatial memory was significantly improved by treatment of NDC (Figure 1B)

Summary

Introduction

Alzheimer’s disease (AD) is the most common type of dementia and has no effective cure so far. Curcumin and its derivatives which are suggested to have therapeutic potential for AD by inhibiting Aβ production and tau phosphorylation (Yang et al, 2005; Necula et al, 2007; Ma et al, 2009), stimulating embryonic neural stem cell proliferation via the MAP kinase pathways, and enhancing adult hippocampal neurogenesis (Kim et al, 2008). They are reported to suppress inflammation process by reducing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)mediated expression of proinflammatory cytokines (Jobin et al, 1999). These studies suggested that multi-target compounds might be promising drug candidates for AD

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Conclusion