scholarly journals Conditional Knockout of Pdha1 in Mouse Hippocampus Impairs Cognitive Function: The Possible Involvement of Lactate

2021 ◽  
Vol 15 ◽  
Author(s):  
Wanxin Chen ◽  
Xiaoxia Sun ◽  
Libin Zhan ◽  
Wen Zhou ◽  
Tingting Bi
Keyword(s):  
Cognitive Function ◽  
Neurodegenerative Diseases ◽  
Hippocampal Neurons ◽  
Morphological Changes ◽  
Quantitative Polymerase Chain Reaction ◽  
Camp Response Element Binding ◽  
Conditional Knockout ◽  
Metabolic Disturbances ◽  
Lactate Accumulation ◽  
Creb Pathway

Background and Purpose: Neurodegenerative diseases are associated with metabolic disturbances. Pyruvate dehydrogenase E1 component subunit alpha (PDHA1) is an essential component in the process of glucose metabolism, and its deficiency exists in various diseases such as Alzheimer’s disease (AD), epilepsy, Leigh’s syndrome, and diabetes-associated cognitive decline. However, the exact role of PDHA1 deficiency in neurodegenerative diseases remains to be elucidated. In this study, we explored the effect of PDHA1 deficiency on cognitive function and its molecular mechanism.Methods: A hippocampus-specific Pdha1 knockout (Pdha1–/–) mouse model was established, and behavioral tests were used to evaluate the cognitive function of mice. Transmission electron microscopy (TEM) was performed to observe the morphological changes of the hippocampus. The lactate level in the hippocampus was measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to explore the possible mechanism of the effect of PDHA1 on cognition.Results:Pdha1 knockout damaged the spatial memory of mice and led to the ultrastructural disorder of hippocampal neurons. Lactate accumulation and abnormal lactate transport occurred in Pdha1–/– mice, and the cyclic AMP-protein kinase A-cAMP response element-binding protein (cAMP/PKA/CREB) pathway was inhibited.Conclusion: Lactate accumulation caused by PDHA1 deficiency in the hippocampus may impair cognitive function by inhibiting the cAMP/PKA/CREB pathway.

scholarly journals Association of Metabolically Healthy and Unhealthy Obesity Phenotypes with Oxidative Stress Parameters and Telomere Length in Healthy Young Adult Men. Analysis of the MAGNETIC Study

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 93
Author(s):  
Mateusz Lejawa ◽  
Kamila Osadnik ◽  
Tadeusz Osadnik ◽  
Natalia Pawlas
Keyword(s):  
Oxidative Stress ◽  
Telomere Length ◽  
Quantitative Polymerase Chain Reaction ◽  
Oxidative Stress Markers ◽  
Metabolic Disturbances ◽  
Total Oxidation ◽  
Stress Markers ◽  
Metabolic Dysregulation ◽  
Total Antioxidant ◽  
Metabolically Healthy

Obesity is a significant factor related to metabolic disturbances that can lead to metabolic syndrome (MetS). Metabolic dysregulation causes oxidative stress, which affects telomere structure. The current study aimed to evaluate the relationships between telomere length, oxidative stress and the metabolically healthy and unhealthy phenotypes in healthy young men. Ninety-eight participants were included in the study (49 healthy slim and 49 obese patients). Study participants were divided into three subgroups according to body mass index and metabolic health. Selected oxidative stress markers were measured in serum. Relative telomere length (rTL) was measured using quantitative polymerase chain reaction. The analysis showed associations between laboratory markers, oxidative stress markers and rTL in metabolically healthy and unhealthy participants. Total oxidation status (TOS), total antioxidant capacity (TAC) and rTL were significantly connected with metabolically unhealthy obesity. TAC was associated with metabolically healthy obesity. Telomeres shorten in patients with metabolic dysregulation related to oxidative stress and obesity linked to MetS. Further studies among young metabolically healthy and unhealthy individuals are needed to determine the pathways related to metabolic disturbances that cause oxidative stress that leads to MetS.

scholarly journals RhoA/ROCK regulation of neuritogenesis via profilin IIa–mediated control of actin stability

2003 ◽  
Vol 162 (7) ◽  
pp. 1267-1279 ◽  
Author(s):  
Jorge Santos Da Silva ◽  
Miguel Medina ◽  
Cecilia Zuliani ◽  
Alessia Di Nardo ◽  
Walter Witke ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Hippocampal Neurons ◽  
Morphological Changes ◽  
Decisive Role ◽  
Central Mechanism ◽  
Actin Binding ◽  
Actin Binding Protein ◽  
Rhoa Activity ◽  
Neuronal Soma ◽  
Cultured Hippocampal Neurons

Neuritogenesis, the first step of neuronal differentiation, takes place as nascent neurites bud from the immediate postmitotic neuronal soma. Little is known about the mechanisms underlying the dramatic morphological changes that characterize this event. Here, we show that RhoA activity plays a decisive role during neuritogenesis of cultured hippocampal neurons by recruiting and activating its specific kinase ROCK, which, in turn, complexes with profilin IIa. We establish that this previously uncharacterized brain-specific actin-binding protein controls neurite sprouting by modifying actin stability, a function regulated by ROCK-mediated phosphorylation. Furthermore, we determine that this novel cascade is switched on or off by physiological stimuli. We propose that RhoA/ROCK/PIIa-mediated regulation of actin stability, shown to be essential for neuritogenesis, may constitute a central mechanism throughout neuronal differentiation.

scholarly journals Post-status epilepticus treatment with the Fyn inhibitor, saracatinib, improves cognitive function in mice

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xin-Ming Luo ◽  
Jing Zhao ◽  
Wen-Yue Wu ◽  
Jie Fu ◽  
Zheng-Yu Li ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Cognitive Function ◽  
Cognitive Deficits ◽  
Tyrosine Kinases ◽  
Hippocampal Neurons ◽  
Water Maze ◽  
Behavioral Tests ◽  
Life Threatening ◽  
The Brain ◽  
Normal Object

Abstract Background Status epilepticus (SE) is a life-threatening neurological disorder. The hippocampus, as an important area of the brain that regulates cognitive function, is usually damaged after SE, and cognitive deficits often result from hippocampal neurons lost after SE. Fyn, a non-receptor Src family of tyrosine kinases, is potentially associated with the onset of seizure. Saracatinib, a Fyn inhibitor, suppresses epileptogenesis and reduces epileptiform spikes. However, whether saracatinib inhibits cognitive deficits after SE is still unknown. Methods In the present study, a pilocarpine-induced SE mouse model was used to answer this question by using the Morris water maze and normal object recognition behavioral tests. Results We found that saracatinib inhibited the loss in cognitive function following SE. Furthermore, we found that the number of hippocampal neurons in the saracatinib treatment group was increased, when compared to the SE group. Conclusions These results showed that saracatinib can improve cognitive functions by reducing the loss of hippocampal neurons after SE, suggesting that Fyn dysfunction is involved in cognitive deficits after SE, and that the inhibition of Fyn is a possible treatment to improve cognitive function in SE patients.

scholarly journals Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity

2020 ◽  
Author(s):  
Alejandro Luarte ◽  
Roberto Henzi ◽  
Anllely Fernández ◽  
Diego Gaete ◽  
Pablo Cisternas ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Hippocampal Neurons ◽  
Morphological Changes ◽  
Morphological Differentiation ◽  
Total Content ◽  
Neuronal Morphology ◽  
Cultured Astrocytes ◽  
Neuronal Proteins ◽  
Dendritic Complexity ◽  
Mirna Content

In the last decades, it has been established that astrocytes play key roles in the regulation of neuronal morphology. However, the contribution of astrocyte-derived small extracellular vesicles (sEVs) to morphological differentiation of neurons has only recently been addressed. Here, we showed that cultured astrocytes expressing a GFP tagged version of the stress-regulated astrocytic enzyme Aldolase C (Aldo C-GFP) release small extracellular vesicles (sEVs) which are transferred into cultured hippocampal neurons. Surprisingly, Aldo C-GFP-containing sEVs (Aldo C-GFP sEVs) displayed an exacerbated capacity to reduce the dendritic complexity in developing hippocampal neurons compared to sEVs derived from control (i.e. GFP-expressing) astrocytes. Using bioinformatics and biochemical tools, we found that the total content of overexpressed Aldo C-GFP correlates with an increased content of endogenous miRNA-26a-5p in both total astrocyte homogenates and sEVs. Notably, neurons magnetofected with a nucleotide sequence that mimics endogenous miRNA-26a-5p (mimic 26a-5p) not only decreased the levels of neuronal proteins associated to morphogenesis regulation and also reproduced morphological changes induced by Aldo-C-GFP sEVs. Furthermore, neurons magnetofected with a sequence targeting miRNA-26a-5p (antago 26a-5p) were largely resistant to Aldo C-GFP sEVs. Our results support a novel and complex level of astrocyte-to-neuron communication mediated by astrocyte-derived sEVs and the activity of their miRNA content.

scholarly journals Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1128
Author(s):  
Maria Kovalska ◽  
Petra Hnilicova ◽  
Dagmar Kalenska ◽  
Anna Tomascova ◽  
Marian Adamkov ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Hippocampal Neurons ◽  
Morphological Changes ◽  
Ischemia Reperfusion ◽  
Immunohistochemical Analysis ◽  
Selective Vulnerability ◽  
Rat Hippocampus ◽  
Resonance Spectroscopy ◽  
Vessel Occlusion ◽  
Global Brain Ischemia

Hyperhomocysteinemia (hHcy) represents a strong risk factor for atherosclerosis-associated diseases, like stroke, dementia or Alzheimer’s disease. A methionine (Met)-rich diet leads to an elevated level of homocysteine in plasma and might cause pathological alterations across the brain. The hippocampus is being constantly studied for its selective vulnerability linked with neurodegeneration. This study explores metabolic and histo-morphological changes in the rat hippocampus after global ischemia in the hHcy conditions using a combination of proton magnetic resonance spectroscopy and magnetic resonance-volumetry as well as immunohistochemical analysis. After 4 weeks of a Met-enriched diet at a dose of 2 g/kg of animal weight/day, adult male Wistar rats underwent 4-vessel occlusion lasting for 15 min, followed by a reperfusion period varying from 3 to 7 days. Histo-morphological analyses showed that the subsequent ischemia-reperfusion insult (IRI) aggravates the extent of the sole hHcy-induced degeneration of the hippocampal neurons. Decreased volume in the grey matter, extensive changes in the metabolic ratio, deeper alterations in the number and morphology of neurons, astrocytes and their processes were demonstrated in the hippocampus 7 days post-ischemia in the hHcy animals. Our results suggest that the combination of the two risk factors (hHcy and IRI) endorses and exacerbates the rat hippocampal neurodegenerative processes.

scholarly journals Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yuki Matsushita ◽  
Yasunari Sakai ◽  
Mitsunori Shimmura ◽  
Hiroshi Shigeto ◽  
Miki Nishio ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Focal Cortical Dysplasia ◽  
Mossy Fibers ◽  
Premature Death ◽  
Mtor Pathway ◽  
Conditional Knockout ◽  
Inhibitory Neurons ◽  
Sequencing Data ◽  
Functional Roles ◽  
Synaptic Markers

Abstract Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8–10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6–8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain.

scholarly journals Pharmacological Transdifferentiation of Human Nasal Olfactory Stem Cells into Dopaminergic Neurons

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Audrey Chabrat ◽  
Emmanuelle Lacassagne ◽  
Rodolphe Billiras ◽  
Sophie Landron ◽  
Amélie Pontisso-Mahout ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Dopaminergic Neurons ◽  
Adult Stem Cells ◽  
Morphological Changes ◽  
Direct Conversion ◽  
Patient Specific ◽  
Induced Pluripotent

The discovery of novel drugs for neurodegenerative diseases has been a real challenge over the last decades. The development of patient- and/or disease-specific in vitro models represents a powerful strategy for the development and validation of lead candidates in preclinical settings. The implementation of a reliable platform modeling dopaminergic neurons will be an asset in the study of dopamine-associated pathologies such as Parkinson’s disease. Disease models based on cell reprogramming strategies, using either human-induced pluripotent stem cells or transcription factor-mediated transdifferentiation, are among the most investigated strategies. However, multipotent adult stem cells remain of high interest to devise direct conversion protocols and establish in vitro models that could bypass certain limitations associated with reprogramming strategies. Here, we report the development of a six-step chemically defined protocol that drives the transdifferentiation of human nasal olfactory stem cells into dopaminergic neurons. Morphological changes were progressively accompanied by modifications matching transcript and protein dopaminergic signatures such as LIM homeobox transcription factor 1 alpha (LMX1A), LMX1B, and tyrosine hydroxylase (TH) expression, within 42 days of differentiation. Phenotypic changes were confirmed by the production of dopamine from differentiated neurons. This new strategy paves the way to develop more disease-relevant models by establishing reprogramming-free patient-specific dopaminergic cell models for drug screening and/or target validation for neurodegenerative diseases.

scholarly journals Corticotropin-releasing hormone (CRH) alters mitochondrial morphology and function by activating the NF-kB-DRP1 axis in hippocampal neurons

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Chiara R. Battaglia ◽  
Silvia Cursano ◽  
Enrico Calzia ◽  
Alberto Catanese ◽  
Tobias M. Boeckers
Keyword(s):  
Hippocampal Neurons ◽  
Morphological Changes ◽  
Mitochondrial Dynamics ◽  
Synaptic Activity ◽  
Mitochondrial Activity ◽  
Mitochondrial Morphology ◽  
Significant Shift ◽  
Corticotropin Releasing Hormone ◽  
Releasing Hormone

AbstractNeuronal stress-adaptation combines multiple molecular responses. We have previously reported that thorax trauma induces a transient loss of hippocampal excitatory synapses mediated by the local release of the stress-related hormone corticotropin-releasing hormone (CRH). Since a physiological synaptic activity relies also on mitochondrial functionality, we investigated the direct involvement of mitochondria in the (mal)-adaptive changes induced by the activation of neuronal CRH receptors 1 (CRHR1). We observed, in vivo and in vitro, a significant shift of mitochondrial dynamics towards fission, which correlated with increased swollen mitochondria and aberrant cristae. These morphological changes, which are associated with increased NF-kB activity and nitric oxide concentrations, correlated with a pronounced reduction of mitochondrial activity. However, ATP availability was unaltered, suggesting that neurons maintain a physiological energy metabolism to preserve them from apoptosis under CRH exposure. Our findings demonstrate that stress-induced CRHR1 activation leads to strong, but reversible, modifications of mitochondrial dynamics and morphology. These alterations are accompanied by bioenergetic defects and the reduction of neuronal activity, which are linked to increased intracellular oxidative stress, and to the activation of the NF-kB/c-Abl/DRP1 axis.

scholarly journals Direct Stimulation of Angiotensin II Type 2 Receptor Enhances Spatial Memory

2011 ◽  
Vol 32 (2) ◽  
pp. 248-255 ◽  
Author(s):  
Fei Jing ◽  
Masaki Mogi ◽  
Akiko Sakata ◽  
Jun Iwanami ◽  
Kana Tsukuda ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Angiotensin Ii ◽  
Neurite Outgrowth ◽  
Hippocampal Neurons ◽  
Receptor Agonist ◽  
Laser Speckle ◽  
Morris Water Maze Test ◽  
Direct Stimulation ◽  
Stimulation Of

We examined the possibility that direct stimulation of the angiotensin II type 2 (AT2) receptor by a newly generated direct AT2 receptor agonist, Compound 21 (C21), enhances cognitive function. Treatment with C21 intraperitoneal injection for 2 weeks significantly enhanced cognitive function evaluated by the Morris water maze test in C57BL6 mice, but this effect was not observed in AT2 receptor-deficient mice. However, C21-induced cognitive enhancement in C57BL6 mice was attenuated by coadministration of icatibant, a bradykinin B2 receptor antagonist. Administration of C21 dose dependently increased cerebral blood flow assessed by laser speckle flowmetry and hippocampal field-excitatory postsynaptic potential (f-EPSP) determined by electrophysiological techniques in C57BL6 mice. Furthermore, activation of the AT2 receptor by C21 promoted neurite outgrowth of cultured hippocampal neurons prepared from fetal transgenic mice expressing green fluorescent protein. Finally, we investigated the pathologic relevance of C21 for spatial learning using an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid-β (1 to 40). We observed that treatment with C21 prevented cognitive decline in this model. These results suggest that a direct AT2 receptor agonist, C21, enhances cognitive function at least owing to an increase in CBF, enhancement of f-EPSP, and neurite outgrowth in hippocampal neurons.

scholarly journals The action of radium on cancer cells. II.—Some factors determining the susceptibility of cancer cells to radium

1933 ◽  
Vol 113 (782) ◽  
pp. 238-250 ◽  
Keyword(s):  
Cancer Cells ◽  
Morphological Changes ◽  
Short Wave ◽  
Wave Radiation ◽  
Metabolic Disturbances ◽  
Normal Tissues ◽  
Lymph Glands ◽  
Different Types ◽  
Points Of View ◽  
Isolated Cell

The susceptibility to radium of different types of cells and tissues is one of the outstanding problems of radiotherapy, both from the theoretical and practical points of view. In the organism, normal and malignant tissues exhibit great variations in their response to short-wave radiation. Some normal tissues, e. g. , lymph glands and tests, are extremely sensitive, while others are much less so. There are similar variations in sensitivity between different malignant new growths when irradiated in the organism. There is, however, more uniformity in the effects of irradiation on normal and malignant tissues when isolated cell-masses are studied. Similar biological and morphological changes are observed after irradiation of tissues cultures, whether of normal fibroblasts or tumour cells; and the metabolic disturbances induced in slice of tumour tissue, tests and spleen are of the same type and magnitude (Crabtree, 1932).

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