scholarly journals Cognitively Impaired Old Mice Display Correlated Reduction in Cortical NMDA Receptor and Complex IV

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 118-118
Author(s):  
Ramkumar Thiyagarajan ◽  
Yonas Redae ◽  
Kenneth Seldeen ◽  
Bruce Troen
Keyword(s):  
Nmda Receptor ◽  
Neuronal Cell ◽  
Learning Ability ◽  
Escape Time ◽  
Mitochondrial Complex ◽  
Bdnf Expression ◽  
Complex Iv ◽  
Aged Mice ◽  
The Impact ◽  
Old Mice

Abstract Cognitive decline in older adults represents a major challenge since cognitive impairment is found in 10% of those ≥ 65 and 50% ≥ 85. Thus it is increasingly important to understand the impact of aging on cognitive health. We performed a battery of tests to assess cognition in 6 month-old (n=12) and 24 month-old (n=8) C57BL/6J mice, equivalent to 30 and 70 year old humans, respectively, and also assessed protein markers in cortex for mitochondrial health and cognition. We found that aged mice displayed fewer spontaneous alternations in the T maze test (p=0.034) and lower recognition of novel objects (p=0.022). In addition, aged mice showed prolonged escape time in the Barnes maze (p=0.035), all of which taken together suggest reduced capacity for learning and recall. Aged mice also exhibited diminished nest building (p<0.001), revealing an impaired functional capacity analogous to the instrumental activities of daily living (IADL) geriatric assessment. We found reduced mitochondrial complex IV expression in the cortices of aged mice concomitant with less expression of N-Methyl D-Aspartate (NMDA) receptor subunits 1, 2A and 2B. The cortices from old mice also exhibited greater expression of immature brain derived neurotrophic factor (pro-BDNF). The alterations in NMDA receptors and pro BDNF are consistent with memory impairment and greater neuronal cell death. Therefore, aged mice exhibit significantly reduced recall and learning ability alongside marked alterations in mitochondrial complex, NMDA receptor, and pro-BDNF expression. Studies are underway to assess whether these molecular changes are responsible for the cognitive declines with aging.

scholarly journals Neuroinflammation in Aged Brain: Impact of the Oral Administration of Ellagic Acid Microdispersion

2020 ◽  
Vol 21 (10) ◽  
pp. 3631 ◽  
Author(s):  
Raffaella Boggia ◽  
Federica Turrini ◽  
Alessandra Roggeri ◽  
Guendalina Olivero ◽  
Francesca Cisani ◽  
...  
Keyword(s):  
Oral Administration ◽  
Ellagic Acid ◽  
Ex Vivo ◽  
Behavioral Skills ◽  
Aged Mice ◽  
Age Related ◽  
The Central Nervous System ◽  
The Impact ◽  
Old Mice

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in “ex-vivo, in vitro” parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.

SOD2 V16A Amplifies Vascular Dysfunction in Sickle Cell Patients by Curtailing Mitochondria Complex IV Activity

Blood ◽  
2021 ◽  
Author(s):  
Atinuke Dosunmu-Ogunbi ◽  
Shuai Yuan ◽  
Michael Reynolds ◽  
Luca Giordano ◽  
Subramaniam Sanker ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Sickle Cell ◽  
Cell Function ◽  
Vascular Dysfunction ◽  
Basal Respiration ◽  
Ros Production ◽  
Mitochondrial Complex ◽  
Complex Iv ◽  
Endothelial Cell Function ◽  
The Impact

Superoxide dismutase 2 (SOD2) catalyzes the dismutation of superoxide to hydrogen peroxide in mitochondria limiting mitochondrial damage. The SOD2 amino acid valine-to-alanine substitution at position 16 (V16A) in the mitochondrial leader sequence is a common genetic variant among patients with sickle cell disease (SCD). However, little is known about the cardiovascular consequences of SOD2V16A in SCD patients or its impact on endothelial cell function. Here, we show SOD2V16A associates with increased tricuspid regurgitant velocity (TRV), systolic blood pressure, right ventricle area at systole and declined 6-minute walk distance in 410 SCD patients. Plasma lactate dehydrogenase, a marker of oxidative stress and hemolysis, significantly associated with higher TRV. To define the impact of SOD2V16A in the endothelium, we introduced the SOD2V16A variant into endothelial cells. SOD2V16A increases hydrogen peroxide and mitochondrial reactive oxygen species (ROS) production compared to controls. Unexpectedly, the increased ROS was not due to SOD2V16A mislocalization but was associated with mitochondrial Complex IV and a concomitant decrease in basal respiration and Complex IV activity. In sum, SOD2V16A is a novel clinical biomarker of cardiovascular dysfunction in SCD patients through its ability to decrease mitochondrial Complex IV activity and amplify ROS production in the endothelium.

scholarly journals Aspirin treatment does not increase microhemorrhage size in young or aged mice

2018 ◽  
Author(s):  
Sandy Chan ◽  
Morgan Brophy ◽  
Nozomi Nishimura ◽  
Chris B. Schaffer
Keyword(s):  
Femtosecond Laser Ablation ◽  
Surrounding Tissue ◽  
Aging Brain ◽  
Older Individuals ◽  
Aged Mice ◽  
Intravenous Heparin ◽  
The Impact ◽  
Old Mice ◽  
The Brain ◽  
Vessel Rupture

AbstractMicrohemorrhages are common in the aging brain and are thought to contribute to cognitive decline and the development of neurodegenerative diseases, such as Alzheimer’s disease. Chronic aspirin therapy is widespread in older individuals and decreases the risk of coronary artery occlusions and stroke. There remains a concern that such aspirin usage may prolong bleeding after a vessel rupture in the brain, leading to larger bleeds that cause more damage to the surrounding tissue. Here, we aimed to understand the influence of aspirin usage on the size of cortical microhemorrhages and explored the impact of age. We used femtosecond laser ablation to rupture arterioles in the cortex of both young (2-5 months old) and aged (18-29 months old) mice dosed on aspirin in their drinking water and measured the extent of penetration of both red blood cells and blood plasma into the surrounding tissue. We found no difference in microhemorrhage size for both young and aged mice dosed on aspirin, as compared to controls (hematoma diameter = 104 +/- 39 (97 +/- 38) μm in controls and 109 +/- 25 (101 +/- 28) μm in aspirin-treated young (aged) mice; mean +/- SD). In contrast, young mice treated with intravenous heparin had an increased hematoma diameter of 136 +/- 44 μm. These data suggest that aspirin does not increase the size of microhemorrhages, supporting the safety of aspirin usage.

Mitochondrial complex IV mutation increases reactive oxygen species production and reduces lifespan in aged mice

2018 ◽  
Vol 225 (4) ◽  
pp. e13214 ◽  
Author(s):  
Gesine Reichart ◽  
Johannes Mayer ◽  
Cindy Zehm ◽  
Timo Kirschstein ◽  
Tursonjan Tokay ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen Species Production ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Mitochondrial Complex ◽  
Complex Iv ◽  
Aged Mice ◽  
Species Production

Fluoxetine Protects against Dendritic Spine Loss in Middle-aged APPswe/PSEN1dE9 Double Transgenic Alzheimer’s Disease Mice

2020 ◽  
Vol 17 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Jing Ma ◽  
Yuan Gao ◽  
Wei Tang ◽  
Wei Huang ◽  
Yong Tang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Early Stage ◽  
Learning Ability ◽  
Middle Aged ◽  
Protein Levels ◽  
Spine Pathology ◽  
The Impact

Background: Studies have suggested that cognitive impairment in Alzheimer’s disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice. Objective: In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice. Results: It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus. Conclusion: These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.

Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease

2020 ◽  
Vol 20 (26) ◽  
pp. 2380-2390 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Abdullah Al Mamun ◽  
Md. Ataur Rahman ◽  
Tapan Behl ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Misfolded Proteins ◽  
Cell Organelles ◽  
The Impact

Objective: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by the extracellular accumulations of amyloid beta (Aβ) as senile plaques and intracellular aggregations of tau in the form of neurofibrillary tangles (NFTs) in specific brain regions. In this review, we focus on the interaction of Aβ and tau with cytosolic proteins and several cell organelles as well as associated neurotoxicity in AD. Summary: Misfolded proteins present in cells accompanied by correctly folded, intermediately folded, as well as unfolded species. Misfolded proteins can be degraded or refolded properly with the aid of chaperone proteins, which are playing a pivotal role in protein folding, trafficking as well as intermediate stabilization in healthy cells. The continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. The neuropathological changes of AD brain include the atypical cellular accumulation of misfolded proteins as well as the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. The mechanism of neurodegeneration in AD that leads to severe neuronal cell death and memory dysfunctions is not completely understood until now. Conclusion: Examining the impact, as well as the consequences of protein misfolding, could help to uncover the molecular etiologies behind the complicated AD pathogenesis.

Smo-Shh signaling activator purmorphamine ameliorates neurobehavioral, molecular, and morphological alterations in an intracerebroventricular propionic acid-induced experimental model of autism

2021 ◽  
pp. 096032712110134
Author(s):  
S Rahi ◽  
R Gupta ◽  
A Sharma ◽  
S Mehan
Keyword(s):  
Propionic Acid ◽  
Developmental Process ◽  
Morphological Changes ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Autism Spectrum ◽  
Neurodevelopmental Disease ◽  
Shh Pathway ◽  
Apoptotic Markers ◽  
The Impact

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disease characterized by cognitive and sensorimotor impairment. Numerous research findings have consistently shown that alteration of Smo-Shh (smoothened-sonic hedgehog) signaling during the developmental process plays a significant role in ASD and triggers neuronal changes by promoting neuroinflammation and apoptotic markers. Purmorphamine (PUR), a small purine-derived agonist of the Smo-Shh pathway, shows resistance to hippocampal neuronal cell oxidation and decreases neuronal cell death. The goal of this study was to investigate the neuroprotective potential of PUR in brain intoxication induced by intracerebroventricular-propionic acid (ICV-PPA) in rats, with a focus on its effect on Smo-Shh regulation in the brain of rats. In addition, we analyze the impact of PUR on myelin basic protein (MBP) and apoptotic markers such as Caspase-3, Bax (pro-apoptotic), and Bcl-2 (anti-apoptotic) in rat brain homogenates. Chronic ICV-PPA infusion was administered consecutively for 11 days to induce autism in rats. In order to investigate behavioral alterations, rats were tested for spatial learning in the Morris Water Maze (MWM), locomotive alterations using actophotometer, and beam crossing task, while Forced Swimming Test (FST) for depressive behavior. PUR treatment with 5 mg/kg and 10 mg/kg (i.p.) was administered from day 12 to 44. Besides cellular, molecular and neuroinflammatory analyses, neurotransmitter levels and oxidative markers have also been studied in brain homogenates. The results of this study have shown that PUR increases the level of Smo-Shh and restores the neurochemical levels, and potentially prevents morphological changes, including demyelination.

Use of Both Fluoro-Jade B and Hematoxylin and Eosin to Detect Cell Death in the Juvenile Rat Brain Exposed to NMDA-Receptor Antagonists or GABA-Receptor Agonists in Safety Assessment

2021 ◽  
pp. 019262332110077
Author(s):  
Catherine A. Picut ◽  
Odete R. Mendes ◽  
David S. Weil ◽  
Sarah Davis ◽  
Cynthia Swanson
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Rat Brain ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Nmda Receptor Antagonists ◽  
Neonatal Rats ◽  
Receptor Antagonists ◽  
Fluoro Jade B ◽  
Hematoxylin And Eosin

Administration of pediatric anesthetics with N-methyl D-aspartate (NMDA)-receptor antagonist and/or γ-aminobutyric acid (GABA) agonist activities may result in neuronal degeneration and/or neuronal cell death in neonatal rats. Evaluating pediatric drug candidates for this potential neurotoxicity is often part of overall preclinical new drug development strategy. This specialized assessment may require dosing neonatal rats at postnatal day 7 at the peak of the brain growth spurt and evaluating brain tissue 24 to 48 hours following dosing. The need to identify methods to aid in the accurate and reproducible detection of lesions associated with this type of neurotoxic profile is paramount for meeting the changing needs of neuropathology assessment and addressing emerging challenges in the neuroscience field. We document the use of Fluoro-Jade B (FJB) staining, to be used in conjunction with standard hematoxylin and eosin staining, to detect acute neurodegeneration and neuronal cell death that can be caused by some NMDA-receptor antagonists and/or GABA agonists in the neonatal rat brain. The FJB staining is simple, specific, and sensitive and can be performed on brain specimens from the same cohort of animals utilized for standard neurotoxicity assessment, thus satisfying animal welfare recommendations with no effect on achievement of scientific and regulatory goals.

scholarly journals A 1-Month Ketogenic Diet Increased Mitochondrial Mass in Red Gastrocnemius Muscle, but not in the Brain or Liver of Middle-Aged Mice

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2533
Author(s):  
Zeyu Zhou ◽  
Jocelyn Vidales ◽  
José A González-Reyes ◽  
Bradley Shibata ◽  
Keith Baar ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Gastrocnemius Muscle ◽  
Left Lobe ◽  
Middle Aged ◽  
Mitochondrial Content ◽  
Mitochondrial Mass ◽  
Aged Mice ◽  
Fractional Area ◽  
Ketogenic Diets ◽  
The Impact

Alterations in markers of mitochondrial content with ketogenic diets (KD) have been reported in tissues of rodents, but morphological quantification of mitochondrial mass using transmission electron microscopy (TEM), the gold standard for mitochondrial quantification, is needed to further validate these findings and look at specific regions of interest within a tissue. In this study, red gastrocnemius muscle, the prefrontal cortex, the hippocampus, and the liver left lobe were used to investigate the impact of a 1-month KD on mitochondrial content in healthy middle-aged mice. The results showed that in red gastrocnemius muscle, the fractional area of both subsarcolemmal (SSM) and intermyofibrillar (IMM) mitochondria was increased, and this was driven by an increase in the number of mitochondria. Mitochondrial fractional area or number was not altered in the liver, prefrontal cortex, or hippocampus following 1 month of a KD. These results demonstrate tissue-specific changes in mitochondrial mass with a short-term KD and highlight the need to study different muscle groups or tissue regions with TEM to thoroughly determine the effects of a KD on mitochondrial mass.

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