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.

scholarly journals Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Fan’ge Kong ◽  
Xue Jiang ◽  
Ruochen Wang ◽  
Siyu Zhai ◽  
Yizhi Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Tau Protein ◽  
Calcium Binding ◽  
Neuroprotective Effect ◽  
Nuclear Factor Κb ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ht22 Cells ◽  
Anti Inflammatory

Abstract Background Neuroinflammation is a principal element in Alzheimer’s disease (AD) pathogenesis, so anti-inflammation may be a promising therapeutic strategy. Forsythoside B (FTS•B), a phenylethanoid glycoside isolated from Forsythiae fructus, has been reported to exert anti-inflammatory effects. However, no studies have reported whether the anti-inflammatory properties of FTS•B have a neuroprotective effect in AD. In the present study, these effects of FTS•B were investigated using amyloid precursor protein/presenilin 1 (APP/PS1) mice, BV-2 cells, and HT22 cells. Methods APP/PS1 mice were administered FTS•B intragastrically for 36 days. Behavioral tests were then carried out to examine cognitive functions, including the Morris water maze, Y maze, and open field experiment. Immunohistochemistry was used to analyze the deposition of amyloid-beta (Aβ), the phosphorylation of tau protein, and the levels of 4-hydroxynonenal, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule 1 in the hippocampus. Proteins that showed marked changes in levels related to neuroinflammation were identified using proteomics and verified using enzyme-linked immunosorbent assay and western blot. BV-2 and HT22 cells were also used to confirm the anti-neuroinflammatory effects of FTS•B. Results In APP/PS1 mice, FTS•B counteracted cognitive decline, ameliorated the deposition of Aβ and the phosphorylation of tau protein, and attenuated the activation of microglia and astrocytes in the cortex and hippocampus. FTS•B affected vital signaling, particularly by decreasing the activation of JNK-interacting protein 3/C-Jun NH2-terminal kinase and suppressing WD-repeat and FYVE-domain-containing protein 1/toll-like receptor 3 (WDFY1/TLR3), further suppressing the activation of nuclear factor-κB (NF-κB) signaling. In BV-2 and HT22 cells, FTS•B prevented lipopolysaccharide-induced neuroinflammation and reduced the microglia-mediated neurotoxicity. Conclusions FTS•B effectively counteracted cognitive decline by regulating neuroinflammation via NF-κB signaling in APP/PS1 mice, providing preliminary experimental evidence that FTS•B is a promising therapeutic agent in AD treatment.

scholarly journals Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer’s disease model

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan Jose Fernandez-Valenzuela ◽  
Raquel Sanchez-Varo ◽  
Clara Muñoz-Castro ◽  
Vanessa De Castro ◽  
Elisabeth Sanchez-Mejias ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroprotective Effect ◽  
Disease Model ◽  
Stabilizing Agents ◽  
Microtubule Stabilization ◽  
Cognitive Improvement ◽  
Epothilone D ◽  
The Impact ◽  
The Brain

Abstract In Alzheimer’s disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aβ) deposits. However, the effect of microtubule stabilizing agents on Aβ pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aβ accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aβ levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aβ pathology.

scholarly journals Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer’s disease

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Irina Belaya ◽  
Mariia Ivanova ◽  
Annika Sorvari ◽  
Marina Ilicic ◽  
Sanna Loppi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physical Exercise ◽  
Neuronal Loss ◽  
Voluntary Exercise ◽  
Glial Fibrillary Acid Protein ◽  
Free Access ◽  
Beneficial Effects ◽  
5Xfad Mice

Abstract Background Increased physical exercise improves cognitive function and reduces pathology associated with Alzheimer’s disease (AD). However, the mechanisms underlying the beneficial effects of exercise in AD on the level of specific brain cell types remain poorly investigated. The involvement of astrocytes in AD pathology is widely described, but their exact role in exercise-mediated neuroprotection warrant further investigation. Here, we investigated the effect of long-term voluntary physical exercise on the modulation of the astrocyte state. Methods Male 5xFAD mice and their wild-type littermates had free access to a running wheel from 1.5 to 7 months of age. A battery of behavioral tests was used to assess the effects of voluntary exercise on cognition and learning. Neuronal loss, impairment in neurogenesis, beta-amyloid (Aβ) deposition, and inflammation were evaluated using a variety of histological and biochemical measurements. Sophisticated morphological analyses were performed to delineate the specific involvement of astrocytes in exercise-induced neuroprotection in the 5xFAD mice. Results Long-term voluntary physical exercise reversed cognitive impairment in 7-month-old 5xFAD mice without affecting neurogenesis, neuronal loss, Aβ plaque deposition, or microglia activation. Exercise increased glial fibrillary acid protein (GFAP) immunoreactivity and the number of GFAP-positive astrocytes in 5xFAD hippocampi. GFAP-positive astrocytes in hippocampi of the exercised 5xFAD mice displayed increases in the numbers of primary branches and in the soma area. In general, astrocytes distant from Aβ plaques were smaller in size and possessed simplified processes in comparison to plaque-associated GFAP-positive astrocytes. Morphological alterations of GFAP-positive astrocytes occurred concomitantly with increased astrocytic brain-derived neurotrophic factor (BDNF) and restoration of postsynaptic protein PSD-95. Conclusions Voluntary physical exercise modulates the reactive astrocyte state, which could be linked via astrocytic BDNF and PSD-95 to improved cognition in 5xFAD hippocampi. The molecular pathways involved in this modulation could potentially be targeted for benefit against AD.

scholarly journals Action of anti-TNF-α drugs on the progression of Alzheimer's disease: A case report

2015 ◽  
Vol 9 (2) ◽  
pp. 196-200 ◽  
Author(s):  
Carlos Henrique Ferreira Camargo ◽  
Filipe Fernandes Justus ◽  
Giuliano Retzlaff ◽  
Marcelo Rezende Young Blood ◽  
Marcelo Derbli Schafranski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Class ◽  
Cognitive Response ◽  
Cognitive Improvement ◽  
Tnf Α ◽  
Patient Reported ◽  
Previously Treated ◽  
The Subject

The aim of this study was to describe a clinical case of a patient with Alzheimer's disease (AD) in use of an anti-TNF-α agent for rheumatoid arthritis (RA). The patient reported is an 81-year-old Caucasian man and retired teacher, diagnosed with RA in 2008 and AD in 2011. Treatment with donepezil was started in 2011 and the use of etanercept introduced in 2012. He was previously treated with adalimumab in 2010 for 18 months. In 2013, the subject was engaged in a clinical trial to assess a complementary non-pharmacological approach for AD, presenting significant cognitive improvement during the follow-up period. We propose the hypothesis of a synergistic effect of anti-TNF-α medication used for the treatment of RA as the cause of the improvement in cognitive response observed. These findings could suggest a possible use of this drug class in the therapeutic management of AD.

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.

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 Exercise Intervention Associated with Cognitive Improvement in Alzheimer’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Meng Ying Cui ◽  
Yang Lin ◽  
Ji Yao Sheng ◽  
Xuewen Zhang ◽  
Ran Ji Cui
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Healthy Aging ◽  
Exercise Intervention ◽  
Early Stage ◽  
Functional Decline ◽  
Cost Effective ◽  
Cognitive Improvement

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with the syndrome of cognitive and functional decline. Pharmacotherapy has always been in a dominant position for the treatment of AD. However, in most cases, drug therapy is accompanied with clinical delays when older adults have suffered from cognitive decline in episodic memory, working memory, and executive function. On the other hand, accumulating evidence suggests that exercise intervention may ameliorate the progression of cognitive impairment in aging ones while the standard strategy is lacking based on different levels of cognitive decline especially in mild cognitive impairment (MCI) and AD. MCI is the preclinical stage of AD in which neurodegeneration may be reversed via neuroplasticity. Therefore, taking exercise intervention in the early stage of MCI and healthy aging at the risk of AD could slow down the process of cognitive impairment and provide a promising cost-effective nonpharmacological therapy to dementia.

Neuroprotective Effect of Physical Exercise in a Mouse Model of Alzheimer’s Disease Induced by β-Amyloid1–40 Peptide

2013 ◽  
Vol 24 (2) ◽  
pp. 148-163 ◽  
Author(s):  
Leandro C. Souza ◽  
Carlos B. Filho ◽  
André T. R. Goes ◽  
Lucian Del Fabbro ◽  
Marcelo G. de Gomes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physical Exercise ◽  
Mouse Model ◽  
Neuroprotective Effect ◽  
Model Of Alzheimer’S Disease

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.

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