scholarly journals Alteration of copper physiology in mice overexpressing the human Menkes protein ATP7A

2006 ◽  
Vol 290 (5) ◽  
pp. R1460-R1467 ◽  
Author(s):  
Bi-Xia Ke ◽  
Roxana M. Llanos ◽  
Magali Wright ◽  
Yolanda Deal ◽  
Julian F. B. Mercer
Keyword(s):  
Transgenic Mice ◽  
Immunohistochemical Analysis ◽  
Menkes Disease ◽  
Cu Deficiency ◽  
Cu Homeostasis ◽  
Menkes Protein ◽  
Old Mice ◽  
The Brain ◽  
Intestinal Enterocytes

The Menkes protein (ATP7A) is defective in the Cu deficiency disorder Menkes disease and is an important contributor to the maintenance of physiological Cu homeostasis. To investigate more fully the role of ATP7A, transgenic mice expressing the human Menkes gene ATP7A from chicken β-actin composite promoter (CAG) were produced. The transgenic mice expressed ATP7A in lung, heart, liver, kidney, small intestine, and brain but displayed no overt phenotype resulting from expression of the human protein. Immunohistochemical analysis revealed that ATP7A was found primarily in the cardiac muscle, smooth muscle of the lung, distal tubules of the kidney, intestinal enterocytes, and patches of hepatocytes, as well as in the hippocampus, cerebellum, and choroid plexus of the brain. In 60-day- and 300-day-old mice, Cu concentrations were reduced in most tissues, consistent with ATP7A playing a role in Cu efflux. The reduction in Cu was most pronounced in the hearts of older T22#2 females (24%), T22#2 males (18%), and T25#5 females (23%), as well as in the brains of 60-day-old T22#2 females and males (23% and 30%, respectively).

scholarly journals Conserved Cu-MicroRNAs in Arabidopsis thaliana Function in Copper Economy under Deficiency

Plants ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 141 ◽  
Author(s):  
Muhammad Shahbaz ◽  
Marinus Pilon
Keyword(s):  
Arabidopsis Thaliana ◽  
Small Rnas ◽  
Wild Type ◽  
Microrna Target ◽  
Electron Carrier ◽  
Cu Deficiency ◽  
Regulatory Circuits ◽  
Transgenic Lines ◽  
Cu Homeostasis

Copper (Cu) is a micronutrient for plants. Three small RNAs, which are up-regulated by Cu deficiency and target transcripts for Cu proteins, are among the most conserved microRNAs in plants. It was hypothesized that these Cu-microRNAs help save Cu for the most essential Cu-proteins under deficiency. Testing this hypothesis has been a challenge due to the redundancy of the Cu microRNAs and the properties of the regulatory circuits that control Cu homeostasis. In order to investigate the role of Cu-microRNAs in Cu homeostasis during vegetative growth, we used a tandem target mimicry strategy to simultaneously inhibit the function of three conserved Cu-microRNAs in Arabidopsis thaliana. When compared to wild-type, transgenic lines that express the tandem target mimicry construct showed reduced Cu-microRNA accumulation and increased accumulation of transcripts that encode Cu proteins. As a result, these mimicry lines showed impaired photosynthesis and growth compared to wild type on low Cu, which could be ascribed to a defect in accumulation of plastocyanin, a Cu-containing photosynthetic electron carrier, which is itself not a Cu-microRNA target. These data provide experimental support for a Cu economy model where the Cu-microRNAs together function to allow maturation of essential Cu proteins under impending deficiency.

scholarly journals Epigenetic mechanism of carbohydrate sulfotransferase 3 (CHST3) downregulation in the aging brain

2019 ◽  
Author(s):  
David Baidoe-Ansah ◽  
M Sadman Sakib ◽  
Shaobo Jia ◽  
Andre Fischer ◽  
Rahul Kaushik ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Brain Plasticity ◽  
Epigenetic Mechanism ◽  
Aging Brain ◽  
Chondroitin Sulfates ◽  
Expression Of Genes ◽  
Bona Fide ◽  
Old Mice ◽  
The Brain

AbstractNeural extracellular matrix (ECM) is a complex molecular meshwork surrounding neurons and glial cells in the extracellular space. Structural and functional state of ECM in the brain is tightly regulated by various components of neural ECM such as hyaluronic acid, chondroitin sulfate proteoglycans, link proteins, tenascins, various matrix-modifying enzymes such as chondroitin sulfate synthases and carbohydrate sulfotransferase together with matrix-degrading enzymes. Age-dependent accumulation of ECM molecules is implicated in the age-associated decline in synaptic and cognitive functions. Understanding age-associated changes in the expression of genes involved in regulating various components of ECM can provide an insight into the role of ECM in the aging brain. Hence, in this study, we compared the expression levels of ECM regulating genes in three groups of mice: 2-3 months old mice (2-3M), 22- to 26-month-old mice (22-26M) and more than 30-month-old mice (>30M). Using qPCR, we discovered that in the hippocampus of >30M old mice, the majority of ECM related genes are downregulated, while genes related to neuroinflammation are highly upregulated. This pattern was accompanied by a decrease in cognitive performance of the >30M old mice and was most correlated among ECM-related genes with the downregulation of carbohydrate sulfotransferase 3 (CHST3) gene expression. Interestingly, in 24-26M mice, no general decrease in the expression of ECM related genes was observed, although we still found the upregulation in neuroinflammatory genes and downregulation of CHST3. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of CHST3 gene in non-neuronal (NeuN-negative) but not in neuronal (NeuN-positive) cells. We conclude that in 22-26 M old brains there are minor changes in expression of the studied bona fide neural ECM genes but there is a prominent epigenetic dysregulation of the CHST3 gene responsible for 6-sulfation of chondroitin sulfates, which may lead to impaired brain plasticity and cognitive decline.

scholarly journals Entry versus Blockade of Brain Infection following Oral or Intraperitoneal Scrapie Administration: Role of Prion Protein Expression in Peripheral Nerves and Spleen

2000 ◽  
Vol 74 (2) ◽  
pp. 828-833 ◽  
Author(s):  
Richard Race ◽  
Michael Oldstone ◽  
Bruce Chesebro
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Peripheral Nerves ◽  
Transmissible Spongiform Encephalopathy ◽  
Spongiform Encephalopathy ◽  
Brain Infection ◽  
Successful Infection ◽  
Scrapie Infection ◽  
The Brain

ABSTRACT Naturally occurring transmissible spongiform encephalopathy (TSE) diseases such as bovine spongiform encephalopathy in cattle are probably transmitted by oral or other peripheral routes of infection. While prion protein (PrP) is required for susceptibility, the mechanism of spread of infection to the brain is not clear. Two prominent possibilities include hematogenous spread by leukocytes and neural spread by axonal transport. In the present experiments, following oral or intraperitoneal infection of transgenic mice with hamster scrapie strain 263K, hamster PrP expression in peripheral nerves was sufficient for successful infection of the brain, and cells of the spleen were not required either as a site of amplification or as transporters of infectivity. The role of tissue-specific PrP expression of foreign PrP in interference with scrapie infection was also studied in these transgenic mice. Peripheral expression of heterologous PrP completely protected the majority of mice from clinical disease after oral or intraperitoneal scrapie infection. Such extensive protection has not been seen in earlier studies on interference, and these results suggested that gene therapy with mutant PrP may be effective in preventing TSE diseases.

scholarly journals 3D Neuronal Mitochondrial Morphology in Axons, Dendrites, and Somata of the Aging Mouse Hippocampus

2021 ◽  
Author(s):  
Julie Faitg ◽  
Clay Lacefield ◽  
Tracey Davey ◽  
Kathryn White ◽  
Ross Laws ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Cell Types ◽  
Aging Brain ◽  
Mitochondrial Morphology ◽  
Mitochondrial Network ◽  
Age Related ◽  
Mouse Hippocampus ◽  
Old Mice ◽  
The Brain

The brain′s ability to process complex informations relies on the constant supply of energy through aerobic respiration by mitochondria. Neurons contain three anatomically distinct compartments – the soma, dendrites, and projecting axons – which have different energetic and biochemical requirements, as well as different mitochondrial morphologies in cultured systems. Here we apply a quantitative three-dimensional electron microscopy approach to map mitochondrial network morphology and complexity in the mouse brain. We examine three neuronal sub–compartments – the soma, dendrites, myelinated axons – in the dentate gyrus and CA1 of the mouse hippocampus, two subregions with distinct principal cell types and functions. We also establish compartment-specific differences in mitochondrial morphology across these cell types between young and old mice, highlighting differences in age-related morphological recalibrations. Overall, these data define the nature of the neuronal mitochondrial network in the mouse hippocampus, providing a foundation to examine the role of mitochondrial morpho–function in the aging brain.

scholarly journals Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase

1998 ◽  
Vol 95 (16) ◽  
pp. 9626-9630 ◽  
Author(s):  
Sébastien Couillard-Després ◽  
Qinzhang Zhu ◽  
Philip C. Wong ◽  
Donald L. Price ◽  
Don W. Cleveland ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Transgenic Mice ◽  
Protective Effect ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Spinal Root ◽  
Old Mice ◽  
H Protein

To investigate the role of neurofilaments in motor neuron disease caused by superoxide dismutase (SOD1) mutations, transgenic mice expressing a amyotrophic lateral sclerosis-linked SOD1 mutant (SOD1G37R) were mated with transgenic mice expressing human neurofilament heavy (NF-H) subunits. Unexpectedly, expression of human NF-H transgenes increased by up to 65%, the mean lifespan of SOD1G37R mice. Microscopic examination corroborated the protective effect of NF-H protein against SOD1 toxicity. Although massive neurodegeneration occurred in 1-yr-old mice expressing SOD1G37R alone, spinal root axons and motor neurons were remarkably spared in doubly SOD1G37R;NF-H-transgenic littermates.

Mouse TonEBP-NFAT5: expression in early development and alternative splicing

2002 ◽  
Vol 282 (5) ◽  
pp. F802-F809 ◽  
Author(s):  
Djikolngar Maouyo ◽  
Jee Y. Kim ◽  
Sang D. Lee ◽  
Yanhong Wu ◽  
Seung K. Woo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Binding Protein ◽  
Embryonic Stem ◽  
Immunohistochemical Analysis ◽  
Mouse Development ◽  
Adult Tissues ◽  
Enhancer Binding Protein ◽  
Activated T Cell ◽  
The Brain

Tonicity-responsive enhancer binding protein (TonEBP)- nuclear factor of activated T cell family 5 is a DNA binding protein that plays a key role in the response of cells to hypertonicity. However, TonEBP is expressed and active in tissues that are in an isotonic milieu. To explore the biological role of TonEBP, we cloned mouse TonEBP that shares 92% of amino acids with the human counterpart. TonEBP is expressed in embryonic stem cells and throughout the stages of fetal development. Immunohistochemical analysis shows expression of TonEBP in most, if not all, developing tissues, including the brain, colon, heart, muscle, and eyes. Widespread alternative splicing in exons 2–4 was detected throughout development and in different adult tissues. As a result, four different polypeptides are produced with different lengths at the NH2terminus. Two of the isoforms differ in their ability to stimulate transcription. In conclusion, the presence of TonEBP mRNA during mouse embryogenesis suggests that TonEBP functions at all stages of mouse development, as well as in isotonic adult tissues.

scholarly journals Western Diet Induces Impairment of Liver-Brain Axis Accelerating Neuroinflammation and Amyloid Pathology in Alzheimer's Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Angelika Wiȩckowska-Gacek ◽  
Anna Mietelska-Porowska ◽  
Dominik Chutorański ◽  
Małgorzata Wydrych ◽  
Jan Długosz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Neurological Diseases ◽  
Amyloid Β ◽  
Western Diet ◽  
Amyloid Pathology ◽  
Old Mice ◽  
The Brain

Alzheimer's disease (AD) is an aging-dependent, irreversible neurodegenerative disorder and the most common cause of dementia. The prevailing AD hypothesis points to the central role of altered cleavage of amyloid precursor protein (APP) and formation of toxic amyloid-β (Aβ) deposits in the brain. The lack of efficient AD treatments stems from incomplete knowledge on AD causes and environmental risk factors. The role of lifestyle factors, including diet, in neurological diseases is now beginning to attract considerable attention. One of them is western diet (WD), which can lead to many serious diseases that develop with age. The aim of the study was to investigate whether WD-derived systemic disturbances may accelerate the brain neuroinflammation and amyloidogenesis at the early stages of AD development. To verify this hypothesis, transgenic mice expressing human APP with AD-causing mutations (APPswe) were fed with WD from the 3rd month of age. These mice were compared to APPswe mice, in which short-term high-grade inflammation was induced by injection of lipopolysaccharide (LPS) and to untreated APPswe mice. All experimental subgroups of animals were subsequently analyzed at 4-, 8-, and 12-months of age. APPswe mice at 4- and 8-months-old represent earlier pre-plaque stages of AD, while 12-month-old animals represent later stages of AD, with visible amyloid pathology. Already short time of WD feeding induced in 4-month-old animals such brain neuroinflammation events as enhanced astrogliosis, to a level comparable to that induced by the administration of pro-inflammatory LPS, and microglia activation in 8-month-old mice. Also, WD feeding accelerated increased Aβ production, observed already in 8-month-old animals. These brain changes corresponded to diet-induced metabolic disorders, including increased cholesterol level in 4-months of age, and advanced hypercholesterolemia and fatty liver disease in 8-month-old mice. These results indicate that the westernized pattern of nourishment is an important modifiable risk factor of AD development, and that a healthy, balanced, diet may be one of the most efficient AD prevention methods.

scholarly journals Role of Plasminogen in Propagation of Scrapie

2005 ◽  
Vol 79 (17) ◽  
pp. 11225-11230 ◽  
Author(s):  
Mario Salmona ◽  
Raffaella Capobianco ◽  
Laura Colombo ◽  
Ada De Luigi ◽  
Giacomina Rossi ◽  
...  
Keyword(s):  
Immunohistochemical Analysis ◽  
Major Effect ◽  
Lymphoid Cells ◽  
Wild Type ◽  
Scrapie Agent ◽  
Significant Difference ◽  
Scrapie Strain ◽  
Scrapie Infection ◽  
The Brain

ABSTRACT To investigate whether plasminogen may feature in scrapie infection, we inoculated plasminogen-deficient (Plg−/−), heterozygous plasminogen-deficient (Plg+/−), and wild-type (Plg+/+) mice by the intracerebral or intraperitoneal (i.p.) route with the RML scrapie strain and monitored the onset of neurological signs of disease, survival time, brain, and accumulation of scrapie disease-associated forms of the prion protein (PrPSc). Only after i.p. inoculation, a slight, although significant, difference in survival (P < 0.05) between Plg−/− and Plg+/+ mice was observed. Neuropathological examination and Western blot analysis were carried out when the first signs of disease appeared in Plg+/+ animals (175 days after i.p. inoculation) and when mice reached the terminal stage of illness. At the onset of symptoms, PrPSc accumulation was higher in the brain and spleen of Plg+/+ and Plg+/− mice than in those of Plg−/− mice, and these differences were paralleled by differences in the severity of spongiform changes and astrogliosis in the cerebral cortex and subcortical gray structures. Immunohistochemical analysis of the spleens before inoculation did not show any impairment of the immune system affecting follicular dendritic or lymphoid cells in Plg−/− mice. Once the disease progressed and mice began to die of infection, differences were no longer apparent in either brains or spleens. In conclusion, our data indicate that plasminogen has no major effect on the survival of scrapie agent-infected mice.

The Role of Mitochondria in the Genesis of Neuroaxonal Dystrophy in the Brains of Aging Mice

1975 ◽  
Vol 33 ◽  
pp. 372-373
Author(s):  
J.E. Johnson
Keyword(s):  
Electron Microscopy ◽  
Present Report ◽  
Light And Electron Microscopy ◽  
Dorsal Column ◽  
Neuroaxonal Dystrophy ◽  
Nucleus Gracilis ◽  
Dystrophic Axons ◽  
The Brain ◽  
Nucleus Cuneatus

Although neuroaxonal dystrophy (NAD) has been examined by light and electron microscopy for years, the nature of the components in the dystrophic axons is not well understood. The present report examines nucleus gracilis and cuneatus (the dorsal column nuclei) in the brain stem of aging mice.Mice (C57BL/6J) were sacrificed by aldehyde perfusion at ages ranging from 3 months to 23 months. Several brain areas and parts of other organs were processed for electron microscopy.At 3 months of age, very little evidence of NAD can be discerned by light microscopy. At the EM level, a few axons are found to contain dystrophic material. By 23 months of age, the entire nucleus gracilis is filled with dystrophic axons. Much less NAD is seen in nucleus cuneatus by comparison. The most recurrent pattern of NAD is an enlarged profile, in the center of which is a mass of reticulated material (reticulated portion; or RP).

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