Novel botanical drug DA-9803 prevents deficits in Alzheimer\u2019s mouse models

Guillaume J Pagnier,Miwon Sohn,Ksenia V Kastanenka,Song-Hyen Choi,Brian J Bacskai,Hyeyeon Soh,Sangzin Choi

doi:10.1186/s13195-018-0338-2

Abstract

BackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by deposition of amyloid plaques and disruption of neural circuitry, leading to cognitive decline. Animal models of AD deposit senile plaques and exhibit structural and functional deficits in neurons and neural networks. An effective treatment would prevent or restore these deficits, including calcium dyshomeostasis observed with in-vivo imaging.MethodsWe examined the effects of DA-9803, a multimodal botanical drug, in 5XFAD and APP/PS1 transgenic mice which underwent daily oral treatment with 30 or 100 mg/kg DA-9803 or vehicle alone. Behavioral testing and longitudinal imaging of amyloid deposits and intracellular calcium in neurons with multiphoton microscopy was performed.ResultsChronic administration of DA-9803 restored behavioral deficits in 5XFAD mice and reduced amyloid-β levels. DA-9803 also prevented progressive amyloid plaque deposition in APP/PS1 mice. Elevated calcium, detected in a subset of neurons before the treatment, was restored and served as a functional indicator of treatment efficacy in addition to the behavioral readout. In contrast, mice treated with vehicle alone continued to progressively accumulate amyloid plaques and calcium overload.ConclusionsIn summary, treatment with DA-9803 prevented structural and functional outcome measures in mouse models of AD. Thus, DA-9803 shows promise as a novel therapeutic approach for Alzheimer’s disease.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by deposition of amyloid plaques and disruption of neural circuitry, leading to cognitive decline
Animals in the 100 mg/kg condition recovered to the levels of wildtype controls (Fig. 1b). 5XFAD mice showed impairment in the passive avoidance task as well, spending 124.8 ± 20.3 seconds in the light compartment before returning to the dark compartment when treated with vehicle compared to 300.0 ± 0.0 seconds for the wildtype mice (Fig. 1c, individual t tests, n = 5 mice/group)
We demonstrated that DA-9803 treatment rescued behavioral deficits, prevented progression of amyloid plaque deposition, and led to clearance of Aβ in transgenic mouse models of AD

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by deposition of amyloid plaques and disruption of neural circuitry, leading to cognitive decline. Transgenic mouse models that overexpress human amyloid precursor protein (APP) develop Aβ-related pathologies such as amyloid plaque deposition similar to those in AD patients [4,5,6]. As these mice age, their cortical neurons exhibit alterations in calcium homeostasis, Pagnier et al Alzheimer's Research & Therapy (2018) 10:11. DA-9803 is a multimodal, botanical therapeutic currently in preclinical development by Dong-A ST that shows nootropic promise It is a well-controlled proprietary extract from Morus alba L. and the surface layer of Poria cocos that contains multiple major and minor active ingredients. The extract, with no obvious indications of toxicity, is a potential drug candidate for the treatment and prevention of AD

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Conclusion