Novel botanical drug DA-9803 prevents deficits in Alzheimer’s mouse models

Background: 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. Methods: 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. Results: 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. Conclusions: 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. Electronic supplementary material The online version of this article (10.1186/s13195-018-0338-2) contains supplementary material, which is available to authorized users

Hippocampus-based contextual memory alters the morphological characteristics of astrocytes in the dentate gyrus

Astrocytes have been reported to exist in two states, the resting and the reactive states. Morphological changes in the reactive state of astrocytes include an increase in thickness and number of processes, and an increase in the size of the cell body. Molecular changes also occur, such as an increase in the expression of glial fibrillary acidic protein (GFAP). However, the morphological and molecular changes during the process of learning and memory have not been elucidated. In the current study, we subjected Fvb/n mice to contextual fear conditioning, and checked for morphological and molecular changes in astrocytes. 1 h after fear conditioning, type II and type III astrocytes exhibited a unique status with an increased number of processes and decreased GFAP expression which differed from the typical resting or reactive state. In addition, the protein level of excitatory excitatory amino acid transporter 2 (EAAT2) was increased 1 h to 24 h after contextual fear conditioning while EAAT1 did not show any alterations. Connexin 43 (Cx43) protein was found to be increased at 24 h after fear conditioning. These data suggest that hippocampus-based contextual memory process induces changes in the status of astrocytes towards a novel status different from typical resting or reactive states. These morphological and molecular changes may be in line with functional changes

Additional file 2: Figure S2. of Novel botanical drug DA-9803 prevents deficits in Alzheimer’s mouse models

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

Additional file 1: Figure S1. of Novel botanical drug DA-9803 prevents deficits in Alzheimer’s mouse models

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

Dendritic Spine Anomalies and PTEN Alterations in a Mouse Model of VPA-induced Autism Spectrum Disorder

Mounting evidence suggests that the etiology of autism spectrum disorders (ASDs) is profoundly influenced by exposure to environmental factors, although the precise molecular and cellular links remain ill-defined. In this study, we examined how exposure to valproic acid (VPA) during pregnancy is associated with an increased incidence of Asp. A mouse model was established by injecting VPA at embryonic day 13, and its behavioral phenotypes including impaired social interaction, increased repetitive behaviors and decreased nociception were observed at postnatal days 21-42. VPA-treated mice showed dysregulation of synaptic structure in cortical neurons, including a reduced proportion of filopodium-type and stubby spines and increased proportions of thin and mushroom-type spines, along with a decreased spine head size. We also found that VPA-treatment led to decreased expression of phosphate and tensin homolog (PTEN) and increased levels of p-AKT protein in the hippocampus and cortex. Our data suggest that there is a correlation between VPA exposure and dysregulation of PTEN with ASD-like behavioral and neuroanatomical changes, and this may be a potential mechanism of VPA-induced ASD. (C) 2017 The Authors. Published by Elsevier Ltd.OAIID:RECH_ACHV_DSTSH_NO:T201713479RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A079472CITE_RATE:4.897DEPT_NM:의과학과EMAIL:[email protected]_YN:YY

Additional file 2: Figure S2. of Hippocampus-based contextual memory alters the morphological characteristics of astrocytes in the dentate gyrus

LAA injection did not affect the motor function. (A) The total distance was examined for both control and LAA group with auto-tracking system in Ethovision. (n = 10). (B) The velocity was calculated for the control and LAA groups with the auto-tracking system in Ethovision (n = 10). (TIF 205 kb

Transient anosmia induces depressive-like and anxiolytic-like behavior and reduces amygdalar corticotropin-releasing hormone in a ZnSO4-induced mouse model

Olfactory loss is known to affect both mood and quality of life. Transient anosmia was induced in mice to study the resulting changes in mood, behavior, and on a molecular level. Transient anosmia was induced by a single intranasal instillation of ZnSO4 in BALB/c mice. Hematoxylin and eosin (HE) staining, and potato chip finding test were performed to confirm olfactory loss. Tail suspension, forced swim, and splash tests were performed to evaluate depression-related behavior; while the open field, and elevated plus maze tests were used to evaluate anxiety-related behavior.The mRNA levels of amygdalar corticotropin-releasing hormone (CRH) and hypothalamic glucocorticoid receptor (GR) were quantified using real-time PCR to confirm relevant molecular change. Olfactory loss was confirmed 1-2.5 weeks after induction, and this loss was subsequently reversed over time. The results of the behavioral tests indicated increased depression-like and reduced anxiety-like behavior at week 1. Accordingly, PCR data identified decreased amygdalar CRH expression at week 1. These results suggest that transient anosmia induces both depressive and anxiolytic behavior as a result of decreased amygdalar CRH in a mouse model of anosmia.OAIID:RECH_ACHV_DSTSH_NO:T201733442RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A079472CITE_RATE:3.235DEPT_NM:의과학과EMAIL:[email protected]_YN:YY

Phloroglucinol Attenuates the Cognitive Deficits of the 5XFAD Mouse Model of Alzheimer’s Disease

<div><p>Alzheimer’s disease (AD) is the most common form of dementia among the elderly. Neuritic plaques whose primary component is amyloid beta peptide (Aβ) and neurofibrillary tangles which are composed of hyperphosphorylated tau, are known to be the neuropathological hallmarks of AD. In addition, impaired synaptic plasticity in neuronal networks is thought to be important mechanism underlying for the cognitive deficits observed in AD. Although various causative factors, including excitotoxicity, mitochondrial dysregulation and oxidative damage caused by Aβ, are involved in early onset of AD, fundamental therapeutics that can modify the progression of this disease are not currently available. In the present study, we investigated whether phloroglucinol (1, 3, 5—trihydroxybenzene), a component of phlorotannins, which are plentiful in <i>Ecklonia cava</i>, a marine brown alga species, displays therapeutic activities in AD. We found that phloroglucinol attenuates the increase in reactive oxygen species (ROS) accumulation induced by oligomeric Aβ_1–42 (Aβ_1–42) treatment in HT-22, hippocampal cell line. In addition, phloroglucinol was shown to ameliorate the reduction in dendritic spine density induced by Aβ_1–42 treatment in rat primary hippocampal neuron cultures_. We also found that the administration of phloroglucinol to the hippocampal region attenuated the impairments in cognitive dysfunction observed in 22-week-old 5XFAD (Tg6799) mice, which are used as an AD animal model. These results indicate that phloroglucinol displays therapeutic potential for AD by reducing the cellular ROS levels.</p></div

Phloroglucinol ameliorates the reduction in the synaptophysin and PSD-95 immunoreactivities induced by Aβ_1–42 in primary hippocampal neuron cultures.

<p>(A) Synaptophysin, PSD-95 and MAP2 immunoreactivities were visualized with immunocytochemistry at DIV 18 in rat primary hippocampal neuron cultures treated with vehicle, phloroglucinol and Aβ_1–42 with or without phloroglucinol treatment. (B) The dendritic segment, outlined with a white box (A), is magnified to delineate spine morphology (B). The scale bars indicate 50 μm (A) and 10 μm (B). Phloroglucinol ameliorated the reduced immuroreactivity observed for synaptophysin and PSD-95 in the rat primary hippocampal neuron cultures treated with Aβ_1–42. Representative images of 7 independent experiments were shown.</p