scholarly journals The Neuroprotective Effect of Byu d Mar 25 in LPS-Induced Alzheimer's Disease Mice Model

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Lan Liu ◽  
Yongcang Zhang ◽  
Liang Tang ◽  
Hua Zhong ◽  
Dunzhu Danzeng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Inflammatory Factors ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
Expression Levels ◽  
Caspase 1 ◽  
Tnf Α

Inflammatory factors play an important role in the pathogenesis of Alzheimer’s disease (AD). Byu d Mar 25 (BM25) has been suggested to have protective effects in the central nervous system. However, the effect of BM25 on AD has not been determined. This study aims to investigate the neuroprotective effect of BM25 in AD. A total of 40 AD model mice were randomly assigned to the following five groups (n = 8 per group): the AD + NS group, the AD + donepezil group, and three AD + BM25 groups treated with either 58.39 mg/kg (AD + BM25-L), 116.77 mg/kg (AD + BM25-M), or 233.54 mg/kg BM25 (AD + BM25-H). The Morris water maze test was performed to assess alterations in spatial learning and memory deficits. Nissl staining was performed to detect Nissl bodies and neuronal damage. The expression of IL-1β and TNF-α was evaluated by ELISA. The protein expression of P-P38, P38, P-IκBα, caspase 1, COX2, and iNOS was determined by western blotting. The expression of Aβ, p-Tau, and CD11b was measured by immunohistochemistry. The mRNA expression levels of IL-1β, TNF-α, COX2, and iNOS were measured by qRT-PCR. Spatial memory significantly improved in the AD + BM25-M and AD + BM25-H groups compared with the AD + NS group ( p < 0.05 ). The expression of Aβ and p-Tau significantly decreased in the AD + BM25-M and AD + BM25-H groups ( p < 0.05 ). The neuron density and hierarchy and number of pyramidal neurons significantly increased in the AD + BM25-M and AD + BM25-H groups ( p < 0.05 ). In addition, the expression levels of CD11b, IL-1β, TNF-α, COX2, iNOS, caspase 1, p-IκBα, and p-P38 significantly decreased in the AD + BM25-M and AD + BM25-H groups ( p < 0.05 ). In conclusion, our findings suggest that BM25 may exert anti-inflammatory and neuroprotective effects in AD model mice by suppressing the activity of microglia and inhibiting the phosphorylation of IκBα and p38 MAPK.

In vivo Evaluation and Alzheimer’s Disease Treatment Outcome of siRNA Loaded Dual Targeting Drug Delivery System

2019 ◽  
Vol 20 (1) ◽  
pp. 56-62 ◽  
Author(s):  
Chi Zhang ◽  
Zhichun Gu ◽  
Long Shen ◽  
Xianyan Liu ◽  
Houwen Lin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Outcome ◽  
Neuroprotective Effect ◽  
Sirna Delivery ◽  
Repeated Administration ◽  
Spatial Learning And Memory ◽  
In Vivo Evaluation

Background: To deliver drugs to treat Alzheimer’s Disease (AD), nanoparticles should firstly penetrate through blood brain barrier, and then target neurons. Methods: Recently, we developed an Apo A-I and NL4 dual modified nanoparticle (ANNP) to deliver beta-amyloid converting enzyme 1 (BACE1) siRNA. Although promising in vitro results were obtained, the in vivo performance was not clear. Therefore, in this study, we further evaluated the in vivo neuroprotective effect and toxicity of the ANNP/siRNA. The ANNP/siRNA was 80.6 nm with good stability when incubated with serum. In vivo, the treatment with ANNP/siRNA significantly improves the spatial learning and memory of APP/PS1 double transgenic mice, as determined by mean escape latency, times of crossing the platform area during the 60 s swimming and the percentage of the distance in the target quadrant. Results and Conclusion: After the treatment, BACE1 RNA level of ANNP/siRNA group was greatly reduced, which contributed a good AD treatment outcome. Finally, after repeated administration, the ANNP/siRNA did not lead to significant change as observed by HE staining of main organs, suggesting the good biocompatibility of ANNP/siRNA. These results demonstrated that the ANNP was a good candidate for AD targeting siRNA delivery.

scholarly journals Caspase-1/IL-1β represses membrane transport of GluA1 by inhibiting the interaction between Stargazin and GluA1 in Alzheimer’s disease

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Xunhu Gu ◽  
Hanjun Wu ◽  
Yuqin Xie ◽  
Lijun Xu ◽  
Xu Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Membrane Transport ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Senile Plaque ◽  
Spatial Learning And Memory ◽  
Memory Ability ◽  
Caspase 1 ◽  
Plaque Deposition

Abstract Background Alzheimer's disease is a neurodegenerative disease. Previous study has reported that caspase-1/IL-1β is closely associated with Alzheimer's disease. However, the biological role of caspase-1/IL-1β in Alzheimer's disease has not been fully elucidated. This study aimed to explore the mechanism of action of caspase-1/IL-1β in Alzheimer's disease. Methods Mouse hippocampal neurones were treated with Aβ1-42 to induce Alzheimer's disease cell model. APP/PS1 mice and Aβ1-42-induced hippocampal neurones were treated with AC-YVAD-CMK (caspase-1 inhibitor). Spatial learning and memory ability of mice were detected by morris water maze. Flow cytometry, TUNEL staining, Thioflavin S staining and immunohistochemistry were performed to examine apoptosis and senile plaque deposition. Enzyme linked immunosorbent assay and western blot were performed to assess the levels of protein or cytokines. Co-Immunoprecipitation was performed to verify the interaction between Stargazin and GluA1. Results AC-YVAD-CMK treatment improved spatial learning and memory ability and reduced senile plaque deposition of APP/PS1 mice. Moreover, AC-YVAD-CMK promoted membrane transport of GluA1 in APP/PS1 mice. In vitro, Aβ1-42-induced hippocampal neurones exhibited an increase in apoptosis and a decrease in the membrane transport of GluA1, which was abolished by AC-YVAD-CMK treatment. In addition, Stargazin interacted with GluA1, which was repressed by caspase-1. Caspase-1/IL-1β inhibited membrane transport of GluA1 by inhibiting the interaction between Stargazin and GluA1. Conclusions Our data demonstrate that caspase-1/IL-1β represses membrane transport of GluA1 by inhibiting the interaction between Stargazin in Alzheimer's disease. Thus, caspase-1/IL-1β may be a target for Alzheimer's disease treatment.

scholarly journals Nrf2 Ablation Promotes Alzheimer’s Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Peng Ren ◽  
Jingwei Chen ◽  
Bingxuan Li ◽  
Mengzhou Zhang ◽  
Bei Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
Related Factor ◽  
Qrt Pcr

Introduction. Alzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein. Accumulating evidence has revealed that the slow progressive deterioration of AD is associated with oxidative stress and chronic inflammation in the brain. Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2), which acts through the Nrf2/ARE pathway, is a key regulator of the antioxidant and anti-inflammatory response. Although recent data show a link between Nrf2 and AD-related cognitive decline, the mechanism is still unknown. Thus, we explored how Nrf2 protects brain cells against the oxidative stress and inflammation of AD in a mouse model of AD (APP/PS1 transgenic (AT) mice) with genetic removal of Nrf2. Methods. The spatial learning and memory abilities of 12-month-old transgenic mice were evaluated using a Morris water maze test. Hippocampal levels of Nrf2, Aβ, and p-tauS404 and of astrocytes and microglia were determined by immunostaining. Inflammatory cytokines were determined by ELISA and quantitative real-time polymerase chain reaction (qRT-PCR). Oxidative stress was measured by 8-hydroxydeoxyguanosine immunohistochemistry, and the antioxidant response was determined by qRT-PCR. Results. The spatial learning and memory abilities of AT mice were impaired after Nrf2 deletion. Aβ and p-tauS404 accumulation was increased in the hippocampus of AT/Nrf2-KO mice. Astroglial and microglial activation was exacerbated, followed by upregulation of the proinflammatory cytokines IL-1β, IL-6, and TNF-α. Conclusion. Our present results show that Nrf2 deficiency aggravates AD-like pathology in AT mice. This phenotype was associated with increased levels of oxidative and proinflammatory markers, which suggests that the Nrf2 pathway may be a promising therapeutic target for AD.

Overexpression of miR-26a-5p Suppresses Tau Phosphorylation and Aβ Accumulation in the Alzheimer’s Disease Mice by Targeting DYRK1A

2020 ◽  
Vol 17 (3) ◽  
pp. 241-248 ◽  
Author(s):  
Yanni Liu ◽  
Lin Wang ◽  
Fuheng Xie ◽  
Xiao Wang ◽  
Yuanyuan Hou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Development ◽  
Tau Phosphorylation ◽  
Luciferase Reporter ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
Latency Time ◽  
Underlying Mechanisms

Objective: It is reported that miR-26a-5p could regulate neuronal development, but its underlying mechanisms in Alzheimer’s disease (AD) progression is unclear. Methods: APP (swe)/PS1 (ΔE9) transgenic mice served as AD mice. Morris water maze test was used to measure the spatial learning and memory ability of mice. The expressions of miR-26a-5p, DYRK1A, phosphorylated-Tau, Aβ40, and Aβ42 were detected. The relationship between miR- 26a-5p and DYRK1A was explored using dual luciferase reporter assay. The effects of miR-26a- 5p on AD mice was determined. Results: AD mice walked a lot of wrong ways to find the platform area and the latency time to reach the platform was longer. There was low expression of MiR-26a-5p in AD mice. Overexpression of miR-26a-5p inhibited Tau phosphorylation and Aβ accumulation. MiR-26a-5p negatively regulated DYRK1A via targeting its 3’UTR. In vivo, increased miR-26a-5p down-regulated Aβ40, Aβ42, p-APP and p-Tau levels in AD mice through decreasing DYRK1A. Meanwhile, the swimming path and the latency time, to reach the platform, was shorten after enhancing miR-26a-5p expression. Conclusion: Overexpression of miR-26a-5p could repress Tau phosphorylation and Aβ accumulation via down-regulating DYRK1A level in AD mice.

Exercise-Mediated Alteration of miR-192-5p Is Associated with Cognitive Improvement in Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Zhaomei Qin ◽  
Xingjun Han ◽  
Jing Ran ◽  
Shanshan Guo ◽  
Lina Lv
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physical Exercise ◽  
Protective Effect ◽  
Exercise Intervention ◽  
Neuroprotective Effect ◽  
Voluntary Exercise ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cognitive Improvement ◽  
Tnf Α

<b><i>Introduction:</i></b> Physical exercise is an important component of managing Alzheimer’s disease (AD). miRNAs can be modulated by exercise intervention. <b><i>Objective:</i></b> The study explored the involvement and potential mechanism of miR-192-5p in the protective effect of physical exercise on AD. <b><i>Methods:</i></b> Ninety AD patients were enrolled, in which 45 cases accepted cycling training for continuous 3 months. The expression changes of miR-192-5p before and after exercise were analyzed by reverse transcription-quantitative PCR. 8-month-old APP/PS1 double Tg mice were used as the AD animal model. Mice in the voluntary exercise (VE) group received VE for 4 weeks. Morris water maze (MWM) test was used to evaluate the learning and memory function. Enzyme-linked immunosorbent assay was used to calculate the level of IL-1β, IL-6, and TNF-α. <b><i>Results:</i></b> AD patients showed elevated MMSE scores, decreased ADAS-cog and NPI-Q scores after 3 months of exercise. miR-192-5p was downregulated in the serum of AD patients and correlated with the levels of MMSE score, ADAS-cog, and NPI-Q score. A positive association was detected between serum miR-192-5p with TNF-α, IL-6, and IL-1β levels. MiR-192-5p is downregulated in the hippocampus tissues of mice after VE. Overexpression of miR-192-5p reversed the neuroprotective effect of exercise on AD in mice and promoted the inflammatory response of AD mice. <b><i>Conclusion:</i></b> MiR-192-5p can be modulated by the exercise intervention and involved in the protective effect of exercise on AD.

Oligodendrocyte generation and maturation in the hippocampus may be a target of fluoxetine for delaying cognitive dysfunction during early Alzheimer’s disease

2020 ◽  
Author(s):  
Yi Zhang ◽  
Feng-lei Chao ◽  
Lei Zhang ◽  
Chun-ni Zhou ◽  
Lin Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Dysfunction ◽  
Laser Scanning ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
Abnormal Increase ◽  
Early Alzheimer’S Disease ◽  
Expression And Activity ◽  
Novel Therapeutic

Abstract Background In the central nervous system, the myelin sheath and the cells that form it—oligodendrocytes—are associated with cognitive function. Oligodendrocyte abnormalities is an important early pathogenic factor of Alzheimer’s disease (AD). However, it is unclear how the hippocampal oligodendrocytes change during early AD and whether early hippocampal oligodendrocyte pathology in AD can be regarded as a novel therapeutic target.Methods To address these questions, we subjected APP/PS1 transgenic mice and nontransgenic littermates to fluoxetine interventions for 2 months. After intervention, the behaviors were assessed with open field test and Morris water maze test, the changes in hippocampal oligodendrocytes were studied using immunohistochemistry, immunofluorescence, unbiased stereological techniques, laser scanning confocal microscope and molecular biotechnology.Results AD mice had an abnormally high number of oligodendrocyte lineage cells (Olig2 + cells) but lower expressions of CNPase and MBP and fewer mature oligodendrocytes (CNPase + cells) in the hippocampus than nontransgenic littermates. Among the oligodendrocyte lineage cells in the hippocampus of AD mice, fewer were mature oligodendrocytes and more were immature oligodendrocytes. Furthermore, decreased expression of SOX10, increased expression of LINGO1 and its ligands, and increased expression and activity of GSK3β might work together to induce oligodendrocyte maturation disorder in the hippocampus of AD mice. Fluoxetine treatment not only delayed the deficiencies in spatial learning and memory ability but also rescued the decrease in mature oligodendrocytes and reversed the abnormal increase in oligodendrocyte lineage cells in the hippocampus of AD mice, potentially by inhibiting the expression of LINGO1 and its ligands, inhibiting the expression and activity of GSK3β, reducing the levels of soluble Aβ40 and Aβ42, reducing β-amyloid plaques, reducing the ratio of oligodendrocytes expressing p16, promoting the expression of SOX10 in oligodendrocytes and promoting the maturation of newborn oligodendrocytes, and then increasing the number of mature oligodendrocytes in the hippocampus of AD mice.Conclusion There is oligodendrocyte maturation disorder in the hippocampus during early AD mice. Fluoxetine exposure during early AD may delay cognitive dysfunction by affecting hippocampal oligodendrocyte generation and maturation. Early hippocampal oligodendrocyte generation and maturation in AD might be regarded as a novel therapeutic target.

The Protective Effect of Notoginsenoside R1 on Isoflurane-Induced Neurological Impairment in the Rats via Regulating miR-29a Expression and Neuroinflammation

2021 ◽  
pp. 1-7
Author(s):  
Meijing Wang ◽  
Hongyan Liu ◽  
Lufeng Xu ◽  
Mengmeng Li ◽  
Ming Zhao
Keyword(s):  
Protective Effect ◽  
Neuroprotective Effect ◽  
Neurological Impairment ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Spatial Learning And Memory ◽  
Sprague Dawley ◽  
Real Time Quantitative Pcr ◽  
Rat Pups ◽  
Tnf Α

<b><i>Introduction:</i></b> Isoflurane inhalation leads to apoptotic neurodegeneration and further results in learning and cognitive dysfunction. Notoginsenoside R1 (NGR1), a major ingredient from Radix notoginseng, has been reported to exert neuroprotective effect during brain or neuron injury. This study aimed to investigate the effect of NGR1 on neurological impairment. <b><i>Methods:</i></b> Sixty-four male Sprague Dawley rat pups (15–20 g) of postnatal day 7 were recruited. Spatial learning and memory were assessed by the Morris water maze test, and the neurological severity score was determined. Real-time quantitative PCR was used to detect the expression levels of microRNA (miR)-29a. Enzyme-linked immunosorbent assay was applied to estimate the levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampal tissues. <b><i>Results:</i></b> NGR1 attenuated neurological impairment induced by isoflurane, shown by the decrease in neurological function score and escape latency and the increase in staying time in the original quadrant in rats. NGR1 reversed the downregulation of miR-29a expression induced by isoflurane treatment. After the treatment of NGR1, the elevated levels of IL-6, TNF-α, and IL-1β induced by isoflurane were all decreased significantly in the hippocampal tissues of rats. Additionally, the repressive action of NGR1 in neurological impairment and neuroinflammation was eliminated by downregulating miR-29a in rats. <b><i>Conclusion:</i></b> NGR1 protects against isoflurane-induced neurological impairment. The protective effect of NGR1 might be achieved by promoting the expression of miR-29a and preventing inflammatory response.

scholarly journals Lycopene-Loaded Microemulsion Regulates Neurogenesis in Rats with Aβ-Induced Alzheimer’s Disease Rats Based on the Wnt/β-catenin Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Wen-jing Ning ◽  
Ren-jun Lv ◽  
Ning Xu ◽  
Xun-yao Hou ◽  
Chao Shen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
Pax6 Gene ◽  
Movement Trajectory ◽  
Gene Expressions ◽  
Qrt Pcr ◽  
Related Proteins

Objective. To investigate the effects of lycopene-loaded microemulsion (LME) on the cognitive function and neurogenesis in the dentate gyrus (DG) of the hippocampus and subventricular (SVZ) region of rats with amyloid β- (Aβ-) induced Alzheimer’s disease (AD) and its mechanism based on the Wnt/β-catenin pathway. Methods. Healthy Wistar rats were divided into four groups: the blank control (CON), AD control, traditional lycopene (LOO), and LME groups. The CON and AD groups were fed with normal saline, while the LOO group was fed with traditional lycopene, and the LME group was fed with lycopene-loaded microemulsion. Behavioral tests were performed after three weeks of gastric administration. Immunofluorescence-labeled cells were used to observe the differentiation and maturation of new nerve cells in the DG of the hippocampus and SVZ region. qRT-PCR and Western blotting detected the expression of neurogenesis genes and Wnt/β-catenin pathway-related proteins, respectively. Results. On the Morris water maze test, LME rats had significantly shortened movement trajectory on the searching platform, reduced escape latency time, and increased residence time on the original platform quadrant. In addition, more LME rats crossed the platform when it was removed. Thus, LME can improve the spatial learning and memory of Aβ-induced AD rats. On qRT-PCR, LME significantly increased Reelin, Nestin, and Pax6 gene expressions, which regulate neurogenesis. Immunofluorescence showed that LME could significantly increase BrdU+, Dcx+, BrdU+/Neun+, BrdU+/Dcx+ cells in the DG and SVZ regions, thus promoting neurogenesis. LME also reduced the number of Iba1+ and Iba1+/BrdU+ cells, thus reducing the neuroinflammatory response. On Western blot, LME upregulated the Wnt/β-catenin pathway by upregulating Wnt3a, β-catenin, Disheveled (Dvl), and p-GSK3β and downregulating p-β-catenin and GSK3β. Conclusion. LME attenuates cognitive impairment in Aβ-induced AD rats by promoting neurogenesis in the hippocampus and SVZ region through upregulating the Wnt/β-catenin pathway.

scholarly journals Delivery of BACE1 siRNA mediated by TARBP-BTP fusion protein reduces β-amyloid deposits in a transgenic mouse model of Alzheimer’s Disease

2016 ◽  
Author(s):  
Mohamed M Haroon ◽  
Kamal Saba ◽  
Venkata H Boddeda ◽  
Jerald M Kumar ◽  
Anant Bahadur Patel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fusion Protein ◽  
Nucleic Acids ◽  
Target Genes ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
Systemic Delivery ◽  
Model Of Alzheimer’S Disease ◽  
Plaque Load

AbstractSystemic delivery of nucleic acids to the central nervous system (CNS) is a major challenge for the development of RNA interference-based therapeutics due to absence of stability, target specificity, non-permeability to the blood-brain barrier (BBB), and mainly due to lack of suitable carriers. Using a designed bi-functional fusion protein TARBP-BTP, very recently we demonstrated knockdown of target genes in the brain of both AβPP-PS1 (Alzheimer’s disease, AD) and wildtype C57BL/6 mice upon systemic delivery of a single dose of siRNA. In this report, we further substantiate this hypothesis through an extended study in AβPP-PS1 mice, which upon treatment with seven doses of β-secretase APP cleaving Enzyme 1 (BACE1) siRNA, led to target-specific effects in the mouse brain. Concomitant gene silencing and consequent reduction in plaque load in the cerebral cortex and hippocampus (>60%) in mice treated with TARBP-BTP:siRNA complex further led to improvement in spatial learning and memory, which was assessed and verified through Morris Water Maze test that revealed significant improvement in cognitive function. Moreover, the treatment did not induce any adverse effects as revealed by the histopathology of different organs. The work validates the efficiency of TARBP-BTP fusion protein as an efficient mediator of RNAi giving considerable scope for future intervention of neurodegenerative disorders of the CNS through the use of short nucleic acids as gene specific inhibitors.

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