Neoline Improves Memory Impairment and Reduces Amyloid-β Level and Tau Phosphorylation Through AMPK Activation in the Mouse Alzheimer’s Disease Model

Background: Alzheimer’s disease (AD) is the most general, chronic, and progressive neurodegenerative senile disorder characterized clinically by progressive cognitive deterioration and memory impairment. Neoline is effective against neuropathic pain models, but the effects of neoline against AD-like phenotypes have not been investigated. Objective: We offer the investigation of the effects of neoline in AD. Methods: In this study, a Tg-APPswe/PS1dE9 AD mouse model was treated orally with neoline at a concentration of 0.5 mg/kg or 0.1 mg/kg starting at 7.5 months and administered for three months, and its anti-AD effects were evaluated. Results: Neoline improved memory and cognition impairments and reduced the number of amyloid-beta plaque and the amount of amyloid-β in the brain of AD mice. Furthermore, neoline reduced the anxiety behavior in the AD mouse model. The chronic administration of neoline also induced AMPK phosphorylation and decreased tau, amyloid-β, and BACE1 expression in the hippocampus. These findings indicate that chronic administration of neoline has therapeutic effects via AMPK activation, and BACE1 downregulation resulted in a decrease in the amyloid-β levels in the brain of Tg-APPswe/PS1dE9 AD mice. Conclusion: Our results suggest that neoline is a therapeutic agent for the cure of neurodegenerative diseases like AD.

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In Vivo Microdialysis in Mice Captures Changes in Alzheimer’s Disease Cerebrospinal Fluid Biomarkers Consistent with Developing Pathology

Journal of Alzheimer s Disease ◽

10.3233/jad-210715 ◽

2021 ◽

pp. 1-14

Author(s):

Christiana Bjorkli ◽

Claire Louet ◽

Trude Helen Flo ◽

Mary Hemler ◽

Axel Sandvig ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Mouse Model ◽

Amyloid Β ◽

Csf Biomarkers ◽

Intracerebral Microdialysis ◽

Preclinical Models ◽

The Brain

Background: Preclinical models of Alzheimer’s disease (AD) can provide valuable insights into the onset and progression of the disease, such as changes in concentrations of amyloid-β (Aβ) and tau in cerebrospinal fluid (CSF). However, such models are currently underutilized due to limited advancement in techniques that allow for longitudinal CSF monitoring. Objective: An elegant way to understand the biochemical environment in the diseased brain is intracerebral microdialysis, a method that has until now been limited to short-term observations, or snapshots, of the brain microenvironment. Here we draw upon patient-based findings to characterize CSF biomarkers in a commonly used preclinical mouse model for AD. Methods: Our modified push-pull microdialysis method was first validated ex vivo with human CSF samples, and then in vivo in an AD mouse model, permitting assessment of dynamic changes of CSF Aβ and tau and allowing for better translational understanding of CSF biomarkers. Results: We demonstrate that CSF biomarker changes in preclinical models capture what is observed in the brain; with a decrease in CSF Aβ observed when plaques are deposited, and an increase in CSF tau once tau pathology is present in the brain parenchyma. We found that a high molecular weight cut-off membrane allowed for simultaneous sampling of Aβ and tau, comparable to CSF collection by lumbar puncture in patients. Conclusion: Our approach can further advance AD and other neurodegenerative research by following evolving neuropathology along the disease cascade via consecutive sampling from the same animal and can additionally be used to administer pharmaceutical compounds and assess their efficacy (Bjorkli, unpublished data).

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Ganoderic Acid A Promotes Amyloid-β Clearance (In Vitro) and Ameliorates Cognitive Deficiency in Alzheimer’s Disease (Mouse Model) Through Autophagy Induced by Activating Axl

International Journal of Molecular Sciences ◽

10.3390/ijms22115559 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5559

Author(s):

Li-Feng-Rong Qi ◽

Shuai Liu ◽

Yu-Ci Liu ◽

Ping Li ◽

Xiaojun Xu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Β ◽

Microglial Cells ◽

Confocal Laser ◽

Ganoderic Acid ◽

Aβ Clearance ◽

Cognitive Deficiency ◽

Ad Mouse Model

Alzheimer’s disease (AD) is thought to be caused by amyloid-β (Aβ) accumulation in the central nervous system due to deficient clearance. The aim of the present study was to investigate the effect of ganoderic acid A (GAA) on Aβ clearance in microglia and its anti-AD activity. Aβ degradation in BV2 microglial cells was determined using an intracellular Aβ clearance assay. GAA stimulated autophagosome formation via the Axl receptor tyrosine kinase (Axl)/RAC/CDC42-activated kinase 1 (Pak1) pathway was determined by Western blot analyses, and fluorescence-labeled Aβ42 was localized in lysosomes in confocal laser microscopy images. The in vivo anti-AD activity of GAA was evaluated by object recognition and Morris water maze (MWM) tests in an AD mouse model following intracerebroventricular injection of aggregated Aβ42. The autophagy level in the hippocampus was assayed by immunohistochemical assessment against microtubule-associated proteins 1A/1B light-chain 3B (LC3B). Intracellular Aβ42 levels were significantly reduced by GAA treatment in microglial cells. Additionally, GAA activated autophagy according to increased LC3B-II levels, with this increased autophagy stimulated by upregulating Axl and Pak1 phosphorylation. The effect of eliminating Aβ by GAA through autophagy was reversed by R428, an Axl inhibitor, or IPA-3, a Pak1 inhibitor. Consistent with the cell-based assay, GAA ameliorated cognitive deficiency and reduced Aβ42 levels in an AD mouse model. Furthermore, LC3B expression in the hippocampus was up-regulated by GAA treatment, with these GAA-specific effects abolished by R428. GAA promoted Aβ clearance by enhancing autophagy via the Axl/Pak1 signaling pathway in microglial cells and ameliorated cognitive deficiency in an AD mouse model.

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Front Cover: Flavonoid‐Derived Human Phenyl‐γ‐Valerolactone Metabolites Selectively Detoxify Amyloid‐β Oligomers and Prevent Memory Impairment in a Mouse Model of Alzheimer's Disease

Molecular Nutrition & Food Research ◽

10.1002/mnfr.202070011 ◽

2020 ◽

Vol 64 (5) ◽

pp. 2070011

Author(s):

Roberta Ruotolo ◽

Ilaria Minato ◽

Pietro La Vitola ◽

Luisa Artioli ◽

Claudio Curti ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Memory Impairment ◽

Amyloid Β ◽

Front Cover ◽

Model Of Alzheimer’S Disease

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Effects of GrandFusion Diet on Cognitive Impairment in Transgenic Mouse Model of Alzheimer’s Disease

Nutrients ◽

10.3390/nu13010117 ◽

2020 ◽

Vol 13 (1) ◽

pp. 117 ◽

Cited By ~ 1

Author(s):

Jin Yu ◽

Hong Zhu ◽

Saeid Taheri ◽

William Mondy ◽

Stephen Perry ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Cathepsin B ◽

Memory Impairment ◽

Chronic Traumatic Encephalopathy ◽

Disease Process ◽

Amyloid Β ◽

Aβ Peptide ◽

Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is the result of the deposition of amyloid β (Aβ) peptide into amyloid fibrils and tau into neurofibrillary tangles. At the present time, there are no possible treatments for the disease. We have recently shown that diets enriched in phytonutrients show protection or limit the extent of damage in a number of neurological disorders. GrandFusion (GF) diets have attenuated the outcomes in animal models of traumatic brain injury, cerebral ischemia, and chronic traumatic encephalopathy. In this study, we investigated the effect of GF diets in a mouse model of AD prior to the development of amyloid plaques to show how this treatment paradigm would alter the accumulation of Aβ peptide and related pathologic changes (i.e., inflammation, cathepsin B, and memory impairment). Administration of GF diets (2–4%) over a period of four months in APP/ΔPS1 double-transgenic mice resulted in attenuation in Aβ peptide levels, reduction of amyloid load, and inflammation, increased cathepsin B expression, and improved spatial orientation. Additionally, treatment with GF diets increased nerve growth factor (NGF) levels in the brain and tempered the memory impairment in the animal model. These data suggest that GF diets may alter the development and progression of the mechanisms associated with the disease process to effectively modify AD pathogenesis.

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Spatial memory deficiency early in 6xTg Alzheimer’s disease mouse model

Scientific Reports ◽

10.1038/s41598-020-79344-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shinwoo Kang ◽

Jinho Kim ◽

Keun-A Chang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Spatial Memory ◽

Amyloid Β ◽

Neuronal Loss ◽

Cognitive Changes ◽

Synaptic Loss ◽

5Xfad Mice ◽

Ad Mouse Model

AbstractAlzheimer’s disease (AD) is mainly characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of neurofibrillary tangles (NFTs). While the recent 5xFAD AD mouse model exhibits many AD-related phenotypes and a relatively early and aggressive amyloid β production, it does not show NFTs. Here, we developed and evaluated a novel AD mouse model (6xTg-AD, 6xTg) by crossbreeding 5xFAD mice with mice expressing mutant (P301L) tau protein (MAPT). Through behavioral and histopathological tests, we analyzed cognitive changes and neuropathology in 6xTg mice compared to their respective parental strains according to age. Spatial memory deficits occurred in 6xTg mice at 2 months of age, earlier than they occurred in 5xFAD mice. Histopathological data revealed aggressive Aβ42 and p-tau accumulation in 6xTg mice. Microglial activation occurred in the cortex and hippocampus of 6xTg mice beginning at 2 months. In 6xTg model mice, the synaptic loss was observed in the cortex from 4 months of age and in the hippocampus from 6 months of age, and neuronal loss appeared in the cortex from 4 months of age and in the hippocampus 6 months of age, earlier than it is observed in the 5xFAD and JNPL3 models. These results showed that each pathological symptom appeared much faster than in their parental animal models. In conclusion, these novel 6xTg-AD mice might be an advanced animal model for studying AD, representing a promising approach to developing effective therapy.

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Flavonoid‐Derived Human Phenyl‐γ‐Valerolactone Metabolites Selectively Detoxify Amyloid‐β Oligomers and Prevent Memory Impairment in a Mouse Model of Alzheimer's Disease

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201900890 ◽

2020 ◽

Vol 64 (5) ◽

pp. 1900890 ◽

Cited By ~ 4

Author(s):

Roberta Ruotolo ◽

Ilaria Minato ◽

Pietro La Vitola ◽

Luisa Artioli ◽

Claudio Curti ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Memory Impairment ◽

Amyloid Β ◽

Model Of Alzheimer’S Disease

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Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer's disease mouse model

Glia ◽

10.1002/glia.23074 ◽

2016 ◽

Vol 64 (12) ◽

pp. 2274-2290 ◽

Cited By ~ 47

Author(s):

Sung Hoon Baik ◽

Seokjo Kang ◽

Sung Min Son ◽

Inhee Mook-Jung

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Death ◽

Mouse Model ◽

Amyloid Β ◽

Plaque Growth ◽

The Brain

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Microglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)

International Journal of Molecular Sciences ◽

10.3390/ijms21030816 ◽

2020 ◽

Vol 21 (3) ◽

pp. 816 ◽

Cited By ~ 2

Author(s):

Elena Salobrar-García ◽

Ana C. Rodrigues-Neves ◽

Ana I. Ramírez ◽

Rosa de Hoz ◽

José A. Fernández-Albarral ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Microglial Cell ◽

Amyloid Β ◽

Microglia Activation ◽

Microglial Cells ◽

Retinal Surface ◽

First Time ◽

The Brain

Alzheimer’s disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-β (Aβ) plaques and protein tau neurofibrillary tangles, which are responsible for brain neuroinflammation mediated by microglial cells. Increasing evidence has shown that the retina can also be affected in AD, presenting some molecular and cellular changes in the brain, such as microglia activation. However, there are only a few studies assessing such changes in the retinal microglia in animal models of AD. These studies use retinal sections, which have some limitations. In this study, we performed, for the first time in a triple-transgenic AD mouse model (3xTg-AD), a quantitative morphometric analysis of microglia activation (using the anti-Iba-1 antibody) in retinal whole-mounts, allowing visualization of the entire microglial cell, as well as its localization along the extension of the retina in different layers. Compared to age-matched animals, the retina of 3xTg-AD mice presents a higher number of microglial cells and a thicker microglial cell body area. Moreover, the microglia migrate, reorient, and retract their processes, changing their localization from a parallel to a perpendicular position relative to the retinal surface. These findings demonstrate clear microglia remodeling in the retina of 3xTg-AD mice.

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