Ameliorating Alzheimer’s-like pathology by Minocycline via inhibiting Cdk5/p25 signaling

2021 ◽  
Vol 19 ◽  
Author(s):  
Yu Zhao ◽  
Chuanling Wang ◽  
Wenbo He ◽  
Zhiyou Cai
Keyword(s):  
Matrix Metalloproteinases ◽  
Cognitive Deficits ◽  
Inflammatory Cytokine ◽  
Underlying Mechanism ◽  
Brain Diseases ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Total Tau ◽  
Maze Test ◽  
Improved Learning

Background: Minocycline has multiple neuroprotective roles in abundant brain diseases, including the prevention and treatment of Alzheimer’s disease (AD). Cdk5/p25 signaling plays an important role in the onset and development of Alzheimer’s-like pathology. The aim of the present work was to further explore the underlying mechanism which minocycline effects on Cdk5/p25 signaling related to the Alzheimer’s-like pathology. Methods: The cognitive function of animals was measured by the Morris water maze test. The levels of Aβ were determined by enzyme-linked immunosorbent assay. The levels of APP, β- and γ-secretases; and the biomarkers of tau (total tau and hyperphosphorylated tau), inflammatory cytokine and matrix metalloproteinases (MMP-2 and MMP-9), biomarkers of synapse and Cdk5/p25 signaling were detected by Western blotting. The biomarkers of synapse, inflammatory cytokine and matrix metalloproteinases (MMP-2 and MMP-9) were also determined by immunofluorescence. Results: Minocycline improved learning and memory in APP/PS1 mice. Minocycline limits the production of Aβ and hyperphosphorylation of tau in the hippocampus, and ameliorates synaptic deficit while minocycline inhibits the activation of Cdk5/p25 signaling, inflammation and activation of matrix metalloproteinases. Conclusion: Minocycline mitigates Alzheimer’s-like pathology via limiting the activation of Cdk5/p25 signaling pathway and improves cognitive deficits.

Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

2019 ◽  
Vol 16 (8) ◽  
pp. 710-722 ◽  
Author(s):  
Xiao-Ying Sun ◽  
Quan-Xiu Dong ◽  
Jie Zhu ◽  
Xun Sun ◽  
Li-Fan Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Synaptic Proteins ◽  
Morris Water Maze Test ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Maze Test ◽  
N2a Cells ◽  
Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

scholarly journals Protective Effects of Centella asiatica on Cognitive Deficits Induced by D-gal/AlCl3 via Inhibition of Oxidative Stress and Attenuation of Acetylcholinesterase Level

Toxics ◽  
2019 ◽  
Vol 7 (2) ◽  
pp. 19 ◽  
Author(s):  
Samaila Chiroma ◽  
Mohamad Baharuldin ◽  
Che Mat Taib ◽  
Zulkhairi Amom ◽  
Saravanan Jagadeesan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Cortex ◽  
Prefrontal Cortex ◽  
Cognitive Deficits ◽  
Neurodegenerative Disorder ◽  
Centella Asiatica ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protective Effects ◽  
Ultrastructural Alteration

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with cholinergic dysfunctions and impaired redox homeostasis. The plant Centella asiatica (CA) is renowned for its nutritional benefits and herbal formulas for promoting health, enhancing cognition, and its neuroprotective effects. The present study aims to investigate the protective role of CA on D-gal/AlCl3-induced cognitive deficits in rats. The rats were divided into six groups and administered with donepezil 1 mg/kg/day, CA (200, 400, and 800 mg/kg/day) and D-gal 60 mg/kg/day + AlCl3 200 mg/kg/day for 10 weeks. The ethology of the rats was evaluated by the Morris water maze test. The levels of acetylcholinesterase (AChE), phosphorylated tau (P-tau), malondialdehyde (MDA) and activities of superoxide dismutase (SOD), in the hippocampus and cerebral cortex were estimated by enzyme-linked immunosorbent assay (ELISA). Additionally, the ultrastructure of the prefrontal cortex of the rats’ was observed using transmission electron microscopy (TEM). Rats administered with D-gal/AlCl3 exhibited cognitive deficits, decreased activities of SOD, and marked increase in AChE and MDA levels. Further, prominent alterations in the ultrastructure of the prefrontal cortex were observed. Conversely, co-administration of CA with D-gal/AlCl3 improved cognitive impairment, decreased AChE levels, attenuated the oxidative stress in hippocampus and cerebral cortex, and prevented ultrastructural alteration of neurons in the prefrontal cortex. Irrespective of the dose of CA administered, the protective effects were comparable to donepezil. In conclusion, this study suggests that CA attenuated the cognitive deficits in rats by restoring cholinergic function, attenuating oxidative stress, and preventing the morphological aberrations.

Berberine Alleviates Amyloid-Beta Pathology in the Brain of APP/PS1 Transgenic Mice via Inhibiting β/γ-Secretases Activity and Enhancing α-Secretases

2018 ◽  
Vol 15 (11) ◽  
pp. 1045-1052 ◽  
Author(s):  
Zhiyou Cai ◽  
Chuanling Wang ◽  
Wenbo He ◽  
Yi Chen
Keyword(s):  
Western Blotting ◽  
Amyloid Beta ◽  
Water Maze ◽  
Senile Plaque ◽  
Memory Deficits ◽  
Brain Diseases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Neuroprotective Effects ◽  
Improved Learning ◽  
The Brain

Background: Berberine (BBR) has neuroprotective effects on many brain diseases, including Alzheimer’s disease (AD). Amyloid -beta (Aβ) senile plaque is the most classical pathological hallmarks of AD. Aβ produces from a sequential cleavage by β-secretase (beta-site amyloid precursor protein cleaving enzyme 1, BACE1) and γ -secretase. The aim of our work was to investigate whether the neuroprotective effects of BBR on AD is related to inhibiting Aβ pathology. Method: The cognitive function of mice was assessed by the Morris water maze (MWM) test. The Aβ levels were determined by enzyme linked immunosorbent assay; the expression of APP, sAPPα, ADAM10 and ADAM17, sAPPβ and BACE1 was detected by Western blotting; and the activity of γ -secretase complex (NCT, PS1, Aph-1α and Pen-2) was determined by Western blotting and immunohistochemistry. Results: BBR improved learning and memory deficits of APP/PS1 mice. BBR decreased Aβ levels in the hippocampus of APP/PS1 mice. BACE1 and sAPP -β levels in the BBR-treated groups were significantly reduced in the hippocampus of AD mice. BBR markedly decreased the expression of PS1, Aph-1α and Pen-2, but had no effect on NCT. The levels of sAPPα, ADAM10 and ADAM17 in the hippocampus of BBR-treated mice significantly increased, compared with the control ones (P<0.05). Conclusion: BBR inhibits the activity of β/γ-secretases, enhances α-secretases, and lowers the Aβ level in the hippocampus of AD mice, and improves Alzheimer’s-like cognitive impairment.

Adiponectin Ameliorates Cognitive Behaviors and in vivo Synaptic Plasticity Impairments in 3xTg-AD Mice

2021 ◽  
pp. 1-15
Author(s):  
Xu-Dong Yan ◽  
Xue-Song Qu ◽  
Jing Yin ◽  
Jin Qiao ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cognitive Deficits ◽  
Morris Water Maze Test ◽  
Amyloid Β Protein ◽  
Maze Test ◽  
Anti Inflammatory ◽  
Electrophysiological Mechanism ◽  
Proinflammatory Factors

Background: Cognitive deficit is mainly clinical characteristic of Alzheimer’s disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-β protein (Aβ) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear. Objective: To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects. Methods: Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10. Results: Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1β, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice. Conclusion: Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice.

Acupuncture Improves Cognitive Deficits and Increases Neuron Density of the Hippocampus in Middle-Aged Samp8 Mice

2012 ◽  
Vol 30 (4) ◽  
pp. 339-345 ◽  
Author(s):  
Guomin Li ◽  
Xuezhu Zhang ◽  
Haiyan Cheng ◽  
Xuemei Shang ◽  
Hui Xie ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Morris Water Maze ◽  
Cognitive Deficits ◽  
Water Maze ◽  
Morris Water Maze Test ◽  
Control Group ◽  
Neuron Loss ◽  
Neuron Density ◽  
Maze Test ◽  
Samp8 Mice

Objectives To examine whether acupuncture could improve cognitive deficits and reduce the loss of neurons in mice models of ageing. Methods Male 7.5-month-old senescence-accelerated mouse prone 8 (SAMP8) and age-matched senescence-resistant inbred strains 1 (SAMR1) were divided into four groups (n=15 per group): SAMP8 acupuncture group (Pa), SAMP8 non-acupuncture point control group (Pn), SAMP8 control group (Pc) and SAMR1 normal control group (Rc). The behaviours were examined by the Morris water maze test and the neuron density in the hippocampus was estimated by the optical fractionator technique. Results The Morris water maze test demonstrated that the cognitive deficits of SAMP8 mice were improved by acupuncture treatment. Neuronal loss was found in hippocampal regions CA1 (−24%), CA3 (−18%) and DG (−28%) of Pc compared with Rc. The neuron number in hippocampal CA3 and DG of the Pa group was significantly increased by therapeutic acupuncture compared with the Pc group. Conclusions Acupuncture improved the cognitive impairment of middle-aged SAMP8 mice which could be attributed to the reduced neuron loss in hippocampal regions CA3 and DG. These results suggest that reducing neuron loss in the hippocampus by acupuncture is a potential therapeutic approach for the treatment of Alzheimer's disease and cognitive impairment diseases.

scholarly journals Xanthoceraside Ameliorates Mitochondrial Dysfunction Contributing to the Improvement of Learning and Memory Impairment in Mice with Intracerebroventricular Injection of Aβ1-42

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Xue-Fei Ji ◽  
Tian-Yan Chi ◽  
Qian Xu ◽  
Xiao-Lu He ◽  
Xiao-Yu Zhou ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Learning And Memory ◽  
Memory Impairment ◽  
Mitochondrial Respiratory Chain ◽  
Morris Water Maze Test ◽  
Mice Model ◽  
Maze Test ◽  
Y Maze ◽  
Abnormal Increase ◽  
Improved Learning

The effects of xanthoceraside on learning and memory impairment were investigated and the possible mechanism associated with the protection of mitochondria was also preliminarily explored in Alzheimer’s disease (AD) mice model induced by intracerebroventricular (i.c.v.) injection of Aβ1-42. The results indicated that xanthoceraside (0.08–0.32 mg/kg) significantly improved learning and memory impairment in Morris water maze test and Y-maze test. Xanthoceraside significantly reversed the aberrant decrease of ATP levels and attenuated the abnormal increase of ROS levels both in the cerebral cortex and hippocampus in mice injected with Aβ1-42. Moreover, xanthoceraside dose dependently reversed the decrease of COX, PDHC, and KGDHC activity in isolated cerebral cortex mitochondria of the mice compared with Aβ1-42 injected model mice. In conclusion, xanthoceraside could improve learning and memory impairment, promote the function of mitochondria, decrease the production of ROS, and inhibit oxidative stress. The improvement effects on mitochondria may be through withstanding the damage of Aβto mitochondrial respiratory chain and the key enzymes in Kreb’s cycle. Therefore, the results from present study and previous study indicate that xanthoceraside could be a competitive candidate for the treatment of AD.

scholarly journals Electroacupuncture Improves Cognitive Deficits through Increasing Regional Cerebral Blood Flow and Alleviating Inflammation in CCI Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Dexiong Han ◽  
Zhe Liu ◽  
Gaimei Wang ◽  
Ying Zhang ◽  
Zemin Wu
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Proinflammatory Cytokines ◽  
Cognitive Deficits ◽  
Regional Cerebral Blood Flow ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Model Group ◽  
Regional Cerebral Blood ◽  
Operation Group

Objective. To investigate the effect of EA on regional cerebral blood flow, cognitive deficits, inflammation, and its probable mechanisms in chronic cerebral ischemia (CCI) rats.Methods. Rats were assigned randomly into sham operation group (sham group) and operation group. For operation group, CCI model was performed using the permanent bilateral common carotid artery occlusion (BCCAO) method, and then rats were further randomly divided into model group and electroacupuncture (EA) group. 2/15 Hz low-frequency pulse electric intervention was applied at “Baihui” and “Dazhui” acupoints in EA group. Four weeks later, Morris water maze test was adopted to assess the cognitive function, using laser Doppler flowmetry to test changes of regional cerebral blood flow (rCBF); double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) to measure proinflammatory cytokines (IL-6, TNF-α, and IL-1β); western blot to test the protein expression quantities of proinflammatory cytokines, JAK2, and STAT3; and RT-PCR to test JAK2 mRNA and STAT3 mRNA in the hippocampus in each group.Results. Compared with the model group, learning and memory abilities and rCBF and IL-6 expression of the EA group enhanced markedly; IL-1βand JAK2 significantly decreased; TNF-αand STAT3 also declined, but the difference was not apparent.Conclusion. Our research suggests that EA can improve cognitive deficits which may be induced by increasing rCBF and anti-inflammatory effect.

Ellagic Acid Administration Negated the Development of Streptozotocin-Induced Memory Deficit in Rats

Drug Research ◽  
2017 ◽  
Vol 67 (07) ◽  
pp. 425-431 ◽  
Author(s):  
Nitin Bansal ◽  
Pushplata Yadav ◽  
Manish Kumar
Keyword(s):  
Morris Water Maze ◽  
Cognitive Deficits ◽  
Ellagic Acid ◽  
Water Maze ◽  
Elevated Plus Maze ◽  
Morris Water Maze Test ◽  
Elevated Plus Maze Test ◽  
Maze Test ◽  
Tnf Α ◽  
Plus Maze

AbstractRampant production of pro-oxidants and inadequate antioxidant availability in brain exert oxidative stress, which in synergism with impaired glucose metabolism and inflammation leads to neurodegeneration and cognitive deficits. Ellagic acid (EGA) is a phenolic compound present in various fruits and is reported to possess robust antioxidant and anti-inflammatory properties. The present study investigated the effect of EGA administration on streptozotocin (STZ) induced dementia in rats. Bilateral intracerebroventricle (ICV) injection of STZ (3 mg/kg) was given to Wistar rats (200 g) on day 1 and 3. EGA (17.5 and 35 mg/kg) was administered orally to rats for 28 days daily. The spatial memory of rats was quantified by using Morris water maze and elevated plus maze. Brain TBARS, GSH and TNF-α were also measured. Administration of EGA prevented the induction of STZ-ICV triggered cognitive deficits as evident by a significant (p<0.05) reduction in mean escape latency during acquisition trial and increased (p<0.05) time spent in target quadrant during retrieval trial in Morris water maze test, and reduction (p<0.05) in transfer latency in elevated plus maze test. Furthermore, both the doses of EGA attenuated STZ-ICV induced rise in brain TBARS as well as TNF-α and simultaneously enhanced the GSH content. Thus, EGA ameliorated STZ-induced dementia by probably restoring the balance between cellular pro-oxidants and anti-oxidants in brain of rats.

Diosgenin Ameliorates Cognition Deficit and Attenuates Oxidative Damage in Senescent Mice Induced by D-Galactose

2011 ◽  
Vol 39 (03) ◽  
pp. 551-563 ◽  
Author(s):  
Chuan-Sung Chiu ◽  
Yung-Jia Chiu ◽  
Lung-Yuan Wu ◽  
Tsung-Chun Lu ◽  
Tai-Hung Huang ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Morris Water Maze ◽  
Water Maze ◽  
Neuroprotective Effect ◽  
Morris Water Maze Test ◽  
Maze Test ◽  
Mice Brain ◽  
Improved Learning ◽  
Endogenous Antioxidant ◽  
The Brain

This study attempted to access the neuroprotective effect of diosgenin on the senescent mice induced by d-galactose (D-gal). The mice in the experiments were orally administered with diosgenin (1, 5, 25 and 125 mg/kg), for four weeks from the sixth week. The learning and memory abilities of the mice in Morris water maze test and the mechanism involved in the neuroprotective effect of diosgenin on the mice brain tissue were investigated. Diosgenin (5, 25 and 125 mg/kg, p.o.) showed significantly improved learning and memory abilities in Morris water maze test compared to D-gal treated mice (200 mg/kg, ten weeks). Diosgenin also increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and decreased the malondialdehyde (MDA) level in the brain of D-gal treated mice. These results indicated that diosgenin has the potential to be a useful treatment for cognitive impairment. In addition, the memory enhancing effect of diosgenin may be partly mediated via enhancing endogenous antioxidant enzymatic activities.

scholarly journals High Methionine Diet-Induced Alzheimer’s Disease like Symptoms Are Accompanied by 5-Methylcytosine Elevated Levels in the Brain

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Tingting Pi ◽  
Shenjiao Wei ◽  
Yongxuan Jiang ◽  
Jing-Shan Shi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Food Intake ◽  
Amyloid Β ◽  
The Body ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ability Test ◽  
Maze Test ◽  
Related Proteins

Background. Excessive or insufficient intake of methionine (Met) causes neuronal dysfunction, neurodegeneration, cerebrovascular dysfunction, vascular leakage, and short-term memory loss, which result in the occurrence of Alzheimer’s disease- (AD-) like symptoms. Objective. To determine the relationship between high methionine diets (HMD) induced AD-like symptoms and 5-methylcytosine (5-mC) level. Methods. C57BL/6J mice were randomly divided into two groups: the control group (Maintain diets) and the model group (2% HMD). Mice were fed with 2% HMD for 9 weeks. Animals were weighed and food intake was recorded weekly. Open field test, nesting ability test, Y maze test, new object recognition test, and Morris water maze test were used to detect the motor, learning, and memory ability. Hematoxylin-eosin (HE) staining was used to observe the damage of cells in hippocampus and cortex. Immunofluorescence (IF) staining was used to detect the expression and distribution of amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and 5-methylcytosine (5-mC) in hippocampus and cortex. Western blotting (WB) was used to determine the expression of Aβ and DNA methyltransferases- (DNMTs-) related proteins in the cortex. Enzyme-linked immunosorbent assay (ELISA) was performed to detect homocysteine (Hcy) level (ELISA). Results. Feeding of HMD decreased the body weight and food intake of mice. Behavioral testing revealed that HMD caused learning, memory, and motor ability impairment in the mice. HE staining results showed that HMD feeding caused damage of hippocampal and cortical neurons, along with disordered cell arrangement, and loss of neurons. Furthermore, HMD increased the contents of Aβ1-40, Aβ1-42, and 5-mC in the hippocampus and cortex. WB results showed that HMD increased the expression of Aβ production-related proteins, such as amyloid precursor protein (APP) and beta-secretase 1 (BACE1), and decreased the expression of Aβ metabolism-related protein in the cortex, including insulin-degrading enzyme (IDE) and neprilysin (NEP). Additionally, the decreased expression of DNA methyltransferase1 (DNMT1) was observed in HMD-treated mice, but there was no significant change of DNMT3a level. ELISA results showed that HMD increased the levels of Hcy in serum. Conclusion. Our result suggested that the HMD can cause neurotoxicity, leading to AD-like symptoms in mice, which may be related to 5-mC elevated.

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