scholarly journals Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

2020 ◽  
Author(s):  
Dongdong Zhang ◽  
Sheng Li ◽  
Liyan Hou ◽  
Lu Jing ◽  
Zhengzheng Ruan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cognitive Decline ◽  
Passive Avoidance ◽  
Cognitive Performance ◽  
Cognitive Deficits ◽  
Water Maze ◽  
Microglial Activation ◽  
Cognitive Impairments ◽  
Synaptic Loss

Abstract BackgroundCognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the life quality of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by over-activated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using rotenone-induced mouse PD model. Methods: To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by morris water maze, objective recognition and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation and apoptosis were determined by immunohistochemistry, Western blot or immunofluorescence staining. The gene expressions of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased abilities of novel objective recognition, passive avoidance, as well as morris water maze performance compared with vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. Time course study revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 or minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in combined PLX3397 or minocycline and rotenone-treated mice compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. ConclusionsTaken together, our findings suggested that microglial activation contributed to cognitive impairments in rotenone-induced mouse PD model via neuroinflammation, oxidative stress and apoptosis, providing novel insight for the immunopathogensis of cognitive deficits in PD.

scholarly journals Microglial activation contributes to cognitive impairments in rotenone-induced mouse Parkinson’s disease model

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Dongdong Zhang ◽  
Sheng Li ◽  
Liyan Hou ◽  
Lu Jing ◽  
Zhengzheng Ruan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cognitive Decline ◽  
Passive Avoidance ◽  
Cognitive Performance ◽  
Cognitive Deficits ◽  
Water Maze ◽  
Microglial Activation ◽  
Cognitive Impairments ◽  
Synaptic Loss

Abstract Background Cognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the quality of life of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by overactivated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using a rotenone-induced mouse PD model. Methods To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by Morris water maze, objective recognition, and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation, and apoptosis were determined by immunohistochemistry and Western blot or immunofluorescence staining. The gene expression of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. Results Rotenone dose-dependently induced cognitive deficits in mice by showing decreased performance of rotenone-treated mice in the novel objective recognition, passive avoidance, and Morris water maze compared with that of vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, and Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. A time course experiment revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 and minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in mice treated with combined PLX3397 or minocycline and rotenonee compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. Conclusions Taken together, our findings suggested that microglial activation contributes to cognitive impairments in a rotenone-induced mouse PD model via neuroinflammation, oxidative stress, and apoptosis, providing novel insight into the immunopathogensis of cognitive deficits in PD.

Protective effect of citicoline against aluminum-induced cognitive impairments in rats

2016 ◽  
Vol 33 (4) ◽  
pp. 308-317 ◽  
Author(s):  
Ahmed O Abdel-Zaher ◽  
Mostafa M Hamdy ◽  
Mahran S Abdel-Rahman ◽  
Doaa H Abd El-hamid
Keyword(s):  
Oxidative Stress ◽  
Protective Effect ◽  
Passive Avoidance ◽  
Morris Water Maze ◽  
Cognitive Deficits ◽  
Aluminum Chloride ◽  
Water Maze ◽  
Cognitive Impairments ◽  
Radial Arm Maze ◽  
Time Required

The potential protective effect of citicoline on aluminum chloride-induced cognitive deficits was investigated in rats. In a Morris water maze, administration of aluminum chloride to rats for 90 days resulted in increased escape latency to reach the platform and decreased swimming speed in acquisition trials. Similarly, in probe trials, the time required to reach the hidden platform was increased and the time spent in the target quadrant was reduced. Also, administration of aluminum chloride to rats for 90 days increased the reference and working memory errors and time required to end the task in the radial arm maze. In addition, this treatment decreased the step-through latency in the passive avoidance test. Concurrently, treatment of rats with aluminum chloride for 90 days increased hippocampal glutamate, malondialdehyde, and nitrite levels and decreased intracellular reduced glutathione level. In the citicoline-treated group, aluminum chloride-induced learning and memory impairments as assessed by the Morris water maze, radial arm maze, and passive avoidance tests were inhibited. At the same time, treatment of rats with citicoline prevented the biochemical alterations induced by aluminum chloride in the hippocampus. It can be concluded that elevation of hippocampal glutamate level with consequent oxidative stress and nitric oxide (NO) overproduction may play an important role in aluminum-induced cognitive impairments. Also, our results suggest, for the first time, that citicoline can protect against the development of these cognitive deficits through inhibition of aluminum-induced elevation of glutamate level, oxidative stress, and NO overproduction in the hippocampus.

MiR-125b-5p Inhibitor Might Protect Against Sevoflurane-induced Cognitive Impairments by Targeting LIMK1

2019 ◽  
Vol 16 (4) ◽  
pp. 382-391
Author(s):  
Jun Xiong ◽  
Huijun Wang ◽  
Feng Mu ◽  
Zhanxue Liu ◽  
Yin Bao ◽  
...  
Keyword(s):  
Morris Water Maze ◽  
Water Maze ◽  
Cognitive Impairments ◽  
Luciferase Reporter ◽  
Morris Water Maze Test ◽  
Sevoflurane Anesthesia ◽  
Lim Domain ◽  
Apoptosis And Inflammation ◽  
Hippocampal Apoptosis

Purpose: Research has shown that exposure to anesthesia might increase the risks of cognitive impairments and learning difficulties. MiR-125b-5p contributed to anesthesia-induced hippocampal apoptosis. However, the role of miR-125b-5p in sevoflurane-induced cognitive impairments remains unclear. Methods: Firstly, sevoflurane was used to establish a rat model and cognitive impairment was detected by the Morris water maze (MWM) test. The hippocampus was observed by HE staining. The lentivirus-miR-125b-5p antagomiR was transfected into rats to decrease miR-125b-5p. The interaction between miR-125b-5p and LIM domain kinase 1 (LIMK1) was confirmed by the luciferase reporter assay. The mRNA and expression levels of related genes and mRNA were examined by the Quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and western blot. Result: Sevoflurane induced the cognitive dysfunction presenting with longer latency time and few platform crossings in rats. Moreover, miR-125b-5p was observed to be up-regulated in both sevoflurane-anesthesia rats and sevoflurane-treated SH-SY5Y cells. More importantly, a decrease in miR-125b-5p could prevent sevoflurane-induced hippocampal apoptosis and inflammation in rats. Moreover, LIMK1 was the target gene of miR-125b-5p. Interestingly, si-LIMK1 could restore the sevoflurane-induced cell apoptosis in SH-SY5Y cells, which was alleviated by miR-125b-5p inhibitor. Finally, the miR-125b-5p inhibitor shortened the time to find the platform and increased the number of platform crossings compared to sevoflurane-anesthesia rats in the Morris water maze test. At the same time, the expression of LIMK1 was dramatically increased. Conclusion: Altogether, these findings suggested that miR-125b-5p inhibitor could protect against the sevoflurane-induced cognitive impairments by targeting LIMK1.

Cognitive profile of patients with Chiari 1 malformation

2020 ◽  
Vol 18 (5) ◽  
pp. 21-24
Author(s):  
E. G. MENDELEVICH ◽  
◽  
R. G. KOKURKINA ◽  
Keyword(s):  
Prefrontal Cortex ◽  
Literature Review ◽  
Executive Functioning ◽  
Emotional Disorders ◽  
Cognitive Deficits ◽  
Cognitive Impairments ◽  
Cognitive Profile ◽  
Cerebellar Dysfunction ◽  
Chiari 1 Malformation

This paper presents literature review on cognitive impairments in patients with CM1, data on which began to be formed in the recent years. Data on the predominant deficit in the structure of executive functioning in patients with CM1 are presented. The genesis of cognitive deficits in patients with CM1 is most often considered in the context of cerebellar dysfunction and damage to the connections of the cerebellum with the prefrontal cortex, which leads to dysmetria of thinking and emotions. Data from other studies are presented that consider the role of additional factors of cognitive dysfunction in CM1, such as pain and emotional disorders.

Pain and major depressive disorder: Associations with cognitive impairment as measured by the THINC-integrated tool (THINC-it)

2017 ◽  
Vol 15 (1) ◽  
pp. 62-67 ◽  
Author(s):  
Danielle S. Cha ◽  
Nicole E. Carmona ◽  
Rodrigo B. Mansur ◽  
Yena Lee ◽  
Hyun Jung Park ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Cognitive Function ◽  
Depressive Disorder ◽  
Cognitive Performance ◽  
Cognitive Deficits ◽  
Preliminary Evidence ◽  
Digit Symbol Substitution Test ◽  
Major Depressive ◽  
Subjective Cognitive Function

AbstractObjectivesTo examine the role of pain on cognitive function in adults with major depressive disorder (MDD).MethodsAdults (18–65) with a Diagnostic and Statistical Manual – Fifth Edition (DSM-5)-defined diagnosis of MDD experiencing a current major depressive episode (MDE) were enrolled (nMDD = 100). All subjects with MDD were matched in age, sex, and years of education to healthy controls (HC) (nHC = 100) for comparison. Cognitive function was assessed using the recently validated THINC-integrated tool (THINC-it), which comprises variants of the choice reaction time (i.e., THINC-it: Spotter), One-Back (i.e., THINC-it: Symbol Check), Digit Symbol Substitution Test (i.e., THINC-it: Codebreaker), Trail Making Test – Part B (i.e., THINC-it: Trails), as well as the Perceived Deficits Questionnaire for Depression – 5-item (i.e., THINC-it: PDQ-5-D). A global index of objective cognitive function was computed using objective measures from the THINC-it, while self-rated cognitive deficits were measured using the PDQ-5-D. Pain was measured using a Visual Analogue Scale (VAS). Regression analyses evaluated the role of pain in predicting objective and subjective cognitive function.ResultsA significant between-group differences on the VAS was observed (p < 0.001), with individuals with MDD reporting higher pain severity as evidenced by higher scores on the VAS than HC. Significant interaction effects were observed between self -rated cognitive deficits and pain ratings (p < 0.001) on objective cognitive performance (after adjusting for MADRS total score), suggesting that pain moderates the association between self-rated and objective cognitive function.ConclusionsResults indicated that pain is associated with increased self-rated and objective cognitive deficits in adults with MDD.ImplicationsThe study herein provides preliminary evidence demonstrating that adults with MDD reporting pain symptomatology and poorer subjective cognitive function is predictive of poorer objective cognitive performance. THINC-it is capable of detecting cognitive dysfunction amongst adults with MDD and pain.

scholarly journals TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Megan C. Bakeberg ◽  
Anastazja M. Gorecki ◽  
Abigail L. Pfaff ◽  
Madison E. Hoes ◽  
Sulev Kõks ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Cognitive Performance ◽  
Disease Onset ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Progression Markers ◽  
The Relationship

AbstractThe translocase of outer mitochondrial membrane 40 (TOMM40) ‘523’ polymorphism has previously been associated with age of Alzheimer’s disease onset and cognitive functioning in non-pathological ageing, but has not been explored as a candidate risk marker for cognitive decline in Parkinson’s disease (PD). Therefore, this longitudinal study investigated the role of the ‘523’ variant in cognitive decline in a patient cohort from the Parkinson’s Progression Markers Initiative. As such, a group of 368 people with PD were assessed annually for cognitive performance using multiple neuropsychological protocols, and were genotyped for the TOMM40 ‘523’ variant using whole-genome sequencing data. Covariate-adjusted generalised linear mixed models were utilised to examine the relationship between TOMM40 ‘523’ allele lengths and cognitive scores, while taking into account the APOE ε genotype. Cognitive scores declined over the 5-year study period and were lower in males than in females. When accounting for APOE ε4, the TOMM40 ‘523’ variant was not robustly associated with overall cognitive performance. However, in APOE ε3/ε3 carriers, who accounted for ~60% of the whole cohort, carriage of shorter ‘523’ alleles was associated with more severe cognitive decline in both sexes, while carriage of the longer alleles in females were associated with better preservation of global cognition and a number of cognitive sub-domains, and with a delay in progression to dementia. The findings indicate that when taken in conjunction with the APOE genotype, TOMM40 ‘523’ allele length is a significant independent determinant and marker for the trajectory of cognitive decline and risk of dementia in PD.

scholarly journals Minocycline Alleviates Abnormal Phagocytosis of Synapses by Microglia in a Mouse Model of Depression

2021 ◽  
Author(s):  
Qiu-Qin Han ◽  
Shi-Yu Shen ◽  
Xiao-Rong Chen ◽  
Adam Pilot ◽  
Ling-Feng Liang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Microglial Activation ◽  
Functional Brain Imaging ◽  
Behavioral Impairment ◽  
Synaptic Loss ◽  
Neuronal Synapses ◽  
Pathological Conditions ◽  
Treatment Of Depression ◽  
Novel Drugs

Abstract Background Depression is an affective disorder characterized by low mood and loss of interest. So far, the mechanism of antidepressants commonly used in clinical practice has proved problematic, thus it is urgent to gain an updated understanding of the pathogenesis of depression and find potential therapeutic targets. As both functional brain imaging studies and autopsy reports indicated that there is indeed a loss of synapses in depressed patients, it is necessary to explore the mechanism of this process. Methods We firstly investigated the effect of CSDS (a mouse model of depression) on behaviors, synapses, microglia, and phagocytosis of synapses by microglia in mice. Then, to confirm the role of microglia in depression, we used minocycline, a microglial activation inhibitor, to study its effect on behaviors and phagocytosis of synapses in stressed mice. Results Our results show that the expression levels of PSD-95 in the hippocampus of CSDS-induced depression mice are significantly reduced, while the microglia are significantly activated. We co-labeled the synaptic protein PSD-95 with the microglia marker Iba-1, and found that the microglia in the hippocampus of stressed mice contained significantly more PSD-95 engulfed puncta, which revealed that microglia in stressed mice abnormally phagocytized synapses. Moreover, our results indicated that minocycline treatment dampened microglial activation, reduced synaptic loss, alleviated behavioral impairment, and reduced abnormal phagocytosis of synapses by microglia in stressed mice. Conclusions Under depressive pathological conditions, the activated microglia may abnormally engulf neuronal synapses causing synaptic loss. Our findings are important for the discovery of novel drugs for the treatment of depression.

Functional (un-)Coupling: Impairment, Compensation, and Future Progression in Alzheimer's Disease

2021 ◽  
pp. 155005942110522
Author(s):  
Jochen A. Mosbacher ◽  
Markus Waser ◽  
Heinrich Garn ◽  
Stephan Seiler ◽  
Carmina Coronel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Cognitive Performance ◽  
Functional Coupling ◽  
General Importance ◽  
Coupling Mechanisms ◽  
Anterior Posterior

Background: Functional (un-)coupling (task-related change of functional connectivity) between different sites of the brain is a mechanism of general importance for cognitive processes. In Alzheimer's disease (AD), prior research identified diminished cortical connectivity as a hallmark of the disease. However, little is known about the relation between the amount of functional (un-)coupling and cognitive performance and decline in AD. Method: Cognitive performance (based on CERAD-Plus scores) and electroencephalogram (EEG)-based functional (un-)coupling measures (connectivity changes from rest to a Face-Name-Encoding task) were assessed in 135 AD patients (age: M = 73.8 years; SD = 9.0). Of these, 68 patients ( M = 73.9 years; SD = 8.9) participated in a follow-up assessment of their cognitive performance 1.5 years later. Results: The amounts of functional (un-)coupling in left anterior-posterior and homotopic interhemispheric connections in beta1-band were related to cognitive performance at baseline (β = .340; p < .001; β = .274; P = .001, respectively). For both markers, a higher amount of functional coupling was associated with better cognitive performance. Both markers also were significant predictors for cognitive decline. However, while patients with greater functional coupling in left anterior-posterior connections declined less in cognitive performance (β = .329; P = .035) those with greater functional coupling in interhemispheric connections declined more (β = −.402; P = .010). Conclusion: These findings suggest an important role of functional coupling mechanisms in left anterior–posterior and interhemispheric connections in AD. Especially the complex relationship with cognitive decline in AD patients might be an interesting aspect for future studies.

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