scholarly journals Sex-dependent effects of amyloid precursor-like protein 2 in the SOD1-G37R transgenic mouse model of MND

2021 ◽  
Author(s):  
Phan H. Truong ◽  
Peter J. Crouch ◽  
James B. W. Hilton ◽  
Catriona A. McLean ◽  
Roberto Cappai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Transgenic Mouse Model ◽  
Muscle Fibres ◽  
Spinal Cord Tissue ◽  
Human Spinal Cord ◽  
End Stage

AbstractMotor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the End-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2−/− mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP family as a potential target for further investigation into the cause and regulation of MND.

scholarly journals Sex Dependent Effects of Amyloid Precursor-Like Protein 2 in The SOD1-G37R Transgenic Mouse Model of MND.

2021 ◽  
Author(s):  
Phan Hong Truong ◽  
Peter J. Crouch ◽  
James B.W. Hilton ◽  
Catriona A. McLean ◽  
Roberto Cappai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Transgenic Mouse Model ◽  
Muscle Fibres ◽  
Spinal Cord Tissue ◽  
Human Spinal Cord ◽  
End Stage

Abstract Introduction: Motor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. Methods In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. Results We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the end-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2-/- mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. Conclusion These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP-family as a potential target for further investigation into the cause and regulation of MND.

scholarly journals Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (22) ◽  
pp. 12256
Author(s):  
Estibaliz González de San Román ◽  
Alberto Llorente-Ovejero ◽  
Jonatan Martínez-Gardeazabal ◽  
Marta Moreno-Rodríguez ◽  
Lydia Giménez-Llort ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fatty Acid ◽  
Motor Cortex ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Transgenic Mouse Model ◽  
Lipid Species ◽  
Triple Transgenic Mouse

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in aging populations. Recently, the regulation of neurolipid-mediated signaling and cerebral lipid species was shown in AD patients. The triple transgenic mouse model (3xTg-AD), harboring βAPPSwe, PS1M146V, and tauP301L transgenes, mimics many critical aspects of AD neuropathology and progressively develops neuropathological markers. Thus, in the present study, 3xTg-AD mice have been used to test the involvement of the neurolipid-based signaling by endocannabinoids (eCB), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) in relation to the lipid deregulation. [35S]GTPγS autoradiography was used in the presence of specific agonists WIN55,212-2, LPA and CYM5442, to measure the activity mediated by CB1, LPA1, and S1P1 Gi/0 coupled receptors, respectively. Consecutive slides were used to analyze the relative intensities of multiple lipid species by MALDI Mass spectrometry imaging (MSI) with microscopic anatomical resolution. The quantitative analysis of the astrocyte population was performed by immunohistochemistry. CB1 receptor activity was decreased in the amygdala and motor cortex of 3xTg-AD mice, but LPA1 activity was increased in the corpus callosum, motor cortex, hippocampal CA1 area, and striatum. Conversely, S1P1 activity was reduced in hippocampal areas. Moreover, the observed modifications on PC, PA, SM, and PI intensities in different brain areas depend on their fatty acid composition, including decrease of polyunsaturated fatty acid (PUFA) phospholipids and increase of species containing saturated fatty acids (SFA). The regulation of some lipid species in specific brain regions together with the modulation of the eCB, LPA, and S1P signaling in 3xTg-AD mice indicate a neuroprotective adaptation to improve neurotransmission, relieve the myelination dysfunction, and to attenuate astrocyte-mediated neuroinflammation. These results could contribute to identify new therapeutic strategies based on the regulation of the lipid signaling in familial AD patients.

scholarly journals Transplantation of Adipose-Derived Stem Cells Alleviates Striatal Degeneration in a Transgenic Mouse Model for Multiple System Atrophy

2020 ◽  
Vol 29 ◽  
pp. 096368972096018
Author(s):  
Christine Chang ◽  
Jen-Wei Liu ◽  
Bo Cheng Chen ◽  
Zhe Sheng Jiang ◽  
Chi Tang Tu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Multiple System Atrophy ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Ex Vivo ◽  
Transgenic Mouse Model ◽  
Intracerebral Injection ◽  
Nigrostriatal Pathway ◽  
Striatal Degeneration

Patients with multiple system atrophy (MSA), a progressive neurodegenerative disorder of adult onset, were found less than 9 years of life expectancy after onset. The disorders include bradykinesia and rigidity commonly seen in Parkinsonism disease and additional signs such as autonomic dysfunction, ataxia, or dementia. In clinical treatments, MSA poorly responds to levodopa, the drug used to remedy Parkinsonism disease. The exact cause of MSA is still unknown, and exploring a therapeutic solution to MSA remains critical. A transgenic mouse model was established to study the feasibility of human adipose-derived stem cell (ADSC) therapy in vivo. The human ADSCs were transplanted into the striatum of transgenic mice via intracerebral injection. As compared with sham control, we reported significantly enhanced rotarod performance of transgenic mice treated with ADSC at an effective dose, 2 × 105 ADSCs/mouse. Our ex vivo feasibility study supported that intracerebral transplantation of ADSC might alleviate striatal degeneration in MSA transgenic mouse model by improving the nigrostriatal pathway for dopamine, activating autophagy for α-synuclein clearance, decreasing inflammatory signal, and further cell apoptosis, improving myelination and cell survival at caudate-putamen.

scholarly journals ALS-Associated SOD1(G93A) Decreases SERCA Pump Levels and Increases Store-Operated Ca2+ Entry in Primary Spinal Cord Astrocytes from a Transgenic Mouse Model

2019 ◽  
Vol 20 (20) ◽  
pp. 5151 ◽  
Author(s):  
Norante ◽  
Peggion ◽  
Rossi ◽  
Martorana ◽  
De Mario ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Nervous System Function ◽  
Serca Pump ◽  
Selective Death ◽  
First Time ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca2+-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca2+ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca2+ indicators, allowing the direct assessment of Ca2+ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca2+-ATPase and lower ER resting Ca2+ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.

scholarly journals RNA-Seq Analysis of Spinal Cord Tissues from hPFN1G118V Transgenic Mouse Model of ALS at Pre-symptomatic and End-Stages of Disease

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Caroline Barham ◽  
Daniel Fil ◽  
Stephanie D. Byrum ◽  
Yasir Rahmatallah ◽  
Galina Glazko ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Rna Seq

scholarly journals Time-of-Flight Secondary Ion Mass Spectrometry Based Molecular Histology of Human Spinal Cord Tissue and Motor Neurons

2013 ◽  
Vol 85 (18) ◽  
pp. 8741-8748 ◽  
Author(s):  
Jörg Hanrieder ◽  
Per Malmberg ◽  
Olle R. Lindberg ◽  
John S. Fletcher ◽  
Andrew G. Ewing
Keyword(s):  
Mass Spectrometry ◽  
Spinal Cord ◽  
Motor Neurons ◽  
Secondary Ion Mass Spectrometry ◽  
Time Of Flight ◽  
Spinal Cord Tissue ◽  
Human Spinal Cord ◽  
Ion Mass Spectrometry ◽  
Secondary Ion

scholarly journals A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an ALS Mouse Model

2020 ◽  
Author(s):  
Julia Post ◽  
Vanessa Kogel ◽  
Anja Schaffrath ◽  
Philipp Lohmann ◽  
Nadim Joni Shah ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Brain Stem ◽  
Transgenic Mouse ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Transgenic Mouse Model ◽  
Lumbar Spinal Cord ◽  
Disease Phenotype ◽  
Model Of Alzheimer’S Disease

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in brain stem and spinal cord. The cause is unknown, but an increasing evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe two treatment studies demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of Alzheimer’s disease (APP/PS1) and in a transgenic mouse model of ALS (SOD1*G93A).Methods:APP/PS1 and SOD1*G93A mice were treated intraperitoneally for four weeks mice with RD2RD2 vs placebo. APP/PS1 brain and plasma samples were histologically and biochemically analysed for inflammatory markers, gliosis and amyloid pathology. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration.Results: Treatment in APP/PS1 mice revealed significant reduction in glial cell activation in the brain and significantly lower levels of inflammatory cytokines in plasma. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both brain stem and lumbar spinal cord but also in a rescue of neurons in the motor cortex. Moreover, behavioural tests revealed that the disease phenotype of SOD1*G93A mice is halted during treatment.Conclusion: Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.

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