Traditional Japanese Herbal Medicine Yokukansan Targets Distinct but Overlapping Mechanisms in Aged Mice and in the 5xFAD Mouse Model of Alzheimer's Disease.

Rahul Kaushik,Oleg Senkov,Jenny Schneeberg,Alexander Dityatev,Michael R Kreutz,Evgeny Morkovin,Alessandro D Confettura

doi:10.3389/fnagi.2018.00411

Abstract

Yokukansan (YKS) is a traditional Japanese herbal medicine that has been used in humans for the treatment of several neurological conditions, such as age-related anxiety and behavioral and psychological symptoms (BPSD) related to multiple forms of dementia, including Alzheimer’s disease (AD). However, the cellular and molecular mechanisms targeted by YKS in the brain are not completely understood. Here, we compared the efficacy of YKS in ameliorating the age- and early-onset familial AD-related behavioral and cellular defects in two groups of animals: 18- to 22-month-old C57BL6/J wild-type mice and 6- to 9-month-old 5xFAD mice, as a transgenic mouse model of this form of AD. Animals were fed food pellets that contained YKS or vehicle. After 1–2 months of YKS treatment, we evaluated the cognitive improvements in both the aged and 5xFAD transgenic mice, and their brain tissues were further investigated to assess the molecular and cellular changes that occurred following YKS intake. Our results show that both the aged and 5xFAD mice exhibited impaired behavioral performance in novel object recognition and contextual fear conditioning (CFC) tasks, which was significantly improved by YKS. Further analyses of the brain tissue from these animals indicated that in aged mice, this improvement was associated with a reduction in astrogliosis, microglia activation and downregulation of the extracellular matrix (ECM), whereas in 5xFAD mice, none of these mechanisms were evident. These results show the differential action of YKS in healthy aged and 5xFAD mice. However, both aged and 5xFAD YKS-treated mice showed increased neuroprotective signaling through protein kinase B/Akt as the common mode of action. Our data suggest that YKS may impart its beneficial effects through Akt signaling in both 5xFAD mice and aged mice, with multiple additional mechanisms potentially contributing to its beneficial effects in aged animals.

Highlights

Aging is a progressive process that is marked by complex and coherent changes
The mice were subsequently sacrificed to isolate the tissue for the histochemical analysis of extracellular matrix (ECM) expression, astrogliosis, microglial activation Aβ-plaque counting and biochemical analysis of various cell signaling mechanisms relevant to aging and Alzheimer’s disease (AD)
The YKS treatment had no effect on the number of correct choices either on phase 1 or phase 2 (p = 0.3090 and p = 0.8446, respectively, two-way analysis of variance (ANOVA); Supplementary Figure S1)

Summary

Introduction

Aging is a progressive process that is marked by complex and coherent changes. In humans, aging is a prime risk factor for many diseases, notably including the major forms of neurodegeneration. Aging is a major determinant of the onset, progression, and pathogenesis of the most common form of dementia, Alzheimer’s disease (AD; Lindsay et al, 2002; Bertram and Tanzi, 2008). Physiological aging and neurodegenerative diseases share many common symptoms, such as diminished cognitive abilities, neuronal loss, decreases in the number and efficacy of synapses, astrogliosis, microglial inflammation and an increase in neural extracellular matrix (ECM) proteins (Geula et al, 1998; Wiese et al, 2012; Végh et al, 2014a; Rodríguez-Arellano et al, 2016; Song and Dityatev, 2018). Present treatments that affect single molecular targets are not sufficiently effective or have a potentially high degree of associated risks (Cummings et al, 2014)

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