The online version of this article (https://doi.org/10.1186/s13195-018-0338-2) contains supplementary material, which is available to authorized users.
Alzheimer’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.
We 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.
Chronic 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.
In 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.
Additional file 1: Figure S1. Showing DA-9803 does not chemically interfere with the binding of methoxy-XO4 to amyloid plaques. A–C Fluorescent images of methoxy-XO4 amyloid plaques after preincubation with (A) DA-9803 (27 sections from one APP/PS1 mouse), (B) PBS (30 sections from one mouse), and (C) vehicle compound (29 sections from one mouse). D Fluorescence intensity of individual amyloid plaques across conditions. Scale bar, 100 μm. Mean ± SEM. (PDF 748 kb)
Additional file 2: Figure S2. Showing methoxy-XO4 stained amyloid plaque burden and MAP2 immunoreactivity in postmortem hippocampus after treatment with vehicle or DA-9803. A–C Fluorescent images of MAP2-positive neurons (A), methoxy-XO4-labeled plaques (B), and colocalization of MAP2 and methoxy-XO4 (C) in APP/PS1 mice treated daily with the vehicle compound (n = 14 sections from seven mice). D–F Fluorescent images of MAP2-positive neurons (D), methoxy-XO4-labeled plaques (E), and colocalization of MAP2 and methoxy-XO4 (F) in APP/PS1 mice treated daily with 100 mg/kg DA-9803 (n = 17 sections from five mice). Scale bar, 100 μm. G Percentage of cortex occupied by methoxy-XO4-positive plaques across conditions. Mean ± SEM. *p < 0.05. (PDF 2111 kb)
Prince M, et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9:6–5. e2. CrossRef
Hsiao K, et al. Correlative memory deficits, A beta elevation, and amyloid plaques in transgenic mice. Science. 1996;274(5284):98. CrossRef
Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006;12(9):1005–15. PubMed
Kastanenka KV, et al. Optical probes for in vivo brain imaging. In: Optical Probes in Biology. CRC Press; 2015. p. 355–76.
Krause DL, Müller N. Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer’s disease. Int J Alzheimers Dis. 2010;2010.
- Novel botanical drug DA-9803 prevents deficits in Alzheimer’s mouse models
Guillaume J. Pagnier
Ksenia V. Kastanenka
Brian J. Bacskai
- BioMed Central