scholarly journals TBK1 interacts with tau and enhances neurodegeneration in tauopathy

2020 ◽  
Author(s):  
Measho H. Abreha ◽  
Shamsideen Ojelade ◽  
Eric B. Dammer ◽  
Zachary T. McEachin ◽  
Duc M. Duong ◽  
...  
Keyword(s):  
Neuronal Loss ◽  
Postmortem Brain ◽  
Chromosome 17 ◽  
Phosphorylation Sites ◽  
Tau Hyperphosphorylation ◽  
Reciprocal Effect ◽  
Full Complement ◽  
The Brain ◽  
Brain Tissues

ABSTRACTOne of the defining pathological features of Alzheimer’s Disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible tau-directed kinases attractive therapeutic targets. The full complement of tau interacting kinases in AD brain and their activity in disease remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in both human AD and familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activity in both AD and FTDP-17 and map the predominant TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activity may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.

scholarly journals Modulator of apoptosis-1 is a potential therapeutic target in acute ischemic injury

2018 ◽  
Vol 39 (12) ◽  
pp. 2406-2418 ◽  
Author(s):  
Su Jing Chan ◽  
Hui Zhao ◽  
Kazuhide Hayakawa ◽  
Chou Chai ◽  
Chong Teik Tan ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Infarct Volume ◽  
Neuronal Loss ◽  
Ischemic Injury ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
In Vivo Models ◽  
The Brain

Modulator of apoptosis 1 (MOAP-1) is a Bax-associating protein highly enriched in the brain. In this study, we examined the role of MOAP-1 in promoting ischemic injuries following a stroke by investigating the consequences of MOAP-1 overexpression or deficiency in in vitro and in vivo models of ischemic stroke. MOAP-1 overexpressing SH-SY5Y cells showed significantly lower cell viability following oxygen and glucose deprivation (OGD) treatment when compared to control cells. Consistently, MOAP-1−/− primary cortical neurons were observed to be more resistant against OGD treatment than the MOAP-1+/+ primary neurons. In the mouse transient middle cerebral artery occlusion (tMCAO) model, ischemia triggered MOAP-1/Bax association, suggested activation of the MOAP-1-dependent apoptotic cascade. MOAP-1−/− mice were found to exhibit reduced neuronal loss and smaller infarct volume 24 h after tMCAO when compared to MOAP-1+/+ mice. Correspondingly, MOAP-1−/− mice also showed better integrity of neurological functions as demonstrated by their performance in the rotarod test. Therefore, both in vitro and in vivo data presented strongly support the conclusion that MOAP-1 is an important apoptotic modulator in ischemic injury. These results may suggest that a reduction of MOAP-1 function in the brain could be a potential therapeutic approach in the treatment of acute stroke.

scholarly journals Artemisinin-treatment in pre-symptomatic APP-PS1 mice increases gephyrin phosphorylation at Ser270: a modification regulating postsynaptic GABAAR density

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Eva Kiss ◽  
Stefan Kins ◽  
Karin Gorgas ◽  
Maret Orlik ◽  
Carolin Fischer ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Sesquiterpene Lactones ◽  
Phosphorylation Sites ◽  
Additional Increase ◽  
Antimalarial Agents ◽  
Gabaergic Synapses ◽  
Protein Density ◽  
Activity Dependent ◽  
The Brain

Abstract Artemisinins, a group of plant-derived sesquiterpene lactones, are efficient antimalarial agents. They also share anti-inflammatory and anti-viral activities and were considered for treatment of neurodegenerative disorders like Alzheimer’s disease (AD). Additionally, artemisinins bind to gephyrin, the multifunctional scaffold of GABAergic synapses, and modulate inhibitory neurotransmission in vitro. We previously reported an increased expression of gephyrin and GABAA receptors in early pre-symptomatic stages of an AD mouse model (APP-PS1) and in parallel enhanced CDK5-dependent phosphorylation of gephyrin at S270. Here, we studied the effects of artemisinin on gephyrin in the brain of young APP-PS1 mice. We detected an additional increase of gephyrin protein level, elevated gephyrin phosphorylation at Ser270, and an increased amount of GABAAR-γ2 subunits after artemisinin-treatment. Interestingly, the CDK5 activator p35 was also upregulated. Moreover, we demonstrate decreased density of postsynaptic gephyrin and GABAAR-γ2 immunoreactivities in cultured hippocampal neurons expressing gephyrin with alanine mutations at two CDK5 phosphorylation sites. In addition, the activity-dependent modulation of synaptic protein density was abolished in neurons expressing gephyrin lacking one or both of these phosphorylation sites. Thus, our results reveal that artemisinin modulates expression as well as phosphorylation of gephyrin at sites that might have important impact on GABAergic synapses in AD.

scholarly journals Efficacy and tolerability of folate-aminopterin therapy in a rat focal model of multiple sclerosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Petri Elo ◽  
Xiang-Guo Li ◽  
Heidi Liljenbäck ◽  
Maria Gardberg ◽  
Olli Moisio ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Folate Receptor ◽  
Mannose Receptor ◽  
Lesion Size ◽  
Postmortem Brain ◽  
Delayed Type Hypersensitivity ◽  
Lesion Development ◽  
Lewis Rats ◽  
The Brain

Abstract Background Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-β (FR-β), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (68Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-β is expressed in the brain of patients with MS. Methods Focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). 68Ga-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-β expression in postmortem brain samples from 5 patients with MS and 5 healthy controls. Results Immunofluorescence and histological analyses revealed significant reductions in FR-β expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected 68Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-β positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples. Conclusions EC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-β-positive cells in chronically active plaques, which suggests that these results may have translational relevance.

scholarly journals Analysis of Long Noncoding RNA and mRNA Expression Profiles in IL-9-Activated Astrocytes and EAE Mice

2018 ◽  
Vol 45 (5) ◽  
pp. 1986-1998 ◽  
Author(s):  
Xiaomei Liu ◽  
Qing Zhang ◽  
Weixiao Wang ◽  
Dongjiao Zuo ◽  
Jing Wang ◽  
...  
Keyword(s):  
Gene Ontology ◽  
Pathway Analysis ◽  
Kegg Pathway ◽  
Expression Profiles ◽  
Astrocyte Activation ◽  
Kegg Pathway Analysis ◽  
The Brain ◽  
Brain Tissues

Background/Aims: Multiple sclerosis (MS) is an autoimmune disease in the central nervous system associated with demyelination and axonal injury. Astrocyte activation is involved in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. This study was designed to find potential lncRNAs in EAE mice and activated astrocytes. Methods: we performed microarray analysis of lncRNAs from the brain tissues of EAE mice and primary mouse astrocytes treated with IL-9(50 ng/ml). 12 lncRNAs were validated through real-time PCR. Gene ontology and KEGG pathway analysis were applied to explore the potential functions of lncRNAs. Results: Differentially expressed 3300 lncRNAs and 3250 mRNAs were in the brain tissues of EAE mice, and 3748 lncRNAs and 3332 mRNAs were in activated astrocytes. Notably, there were 2 co-up-regulated lncRNAs and 3 co-down-regulated lncRNAs both in the brain tissues of EAE mice and in activated astrocytes, including Gm14005, Gm12478, mouselincRNA1117, AK080435, and mouselincRNA0681, which regulate the ER calcium flux kinetics, zinc finger protein and cell apoptosis. Similarly, there were 7 mRNAs co-up-regulated and 2 mRNAs co-down-regulated both in vivo and in vitro. Gene ontology and KEGG pathway analysis showed that the biological functions of differentially expressed mRNAs were associated with metabolism, development and inflammation. The results of realtime PCR validation were consistent with the data from the microarrays. Conclusions: Our data uncovered the expression profiles of lncRNAs and mRNAs in vivo and in vitro, which may help delineate the mechanisms of astrocyte activation during MS/EAE process.

scholarly journals Functional Implications of Glycogen Synthase Kinase-3-Mediated Tau Phosphorylation

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Diane P. Hanger ◽  
Wendy Noble
Keyword(s):  
Glycogen Synthase ◽  
Regulatory Element ◽  
Tau Phosphorylation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Phosphorylation Sites ◽  
Pick Bodies ◽  
Functional Implications ◽  
The Brain

Tau is primarily a neuronal microtubule-associated protein that has functions related to the stabilisation of microtubules. Phosphorylation of tau is an important dynamic and regulatory element involved in the binding of tau to tubulin. Thus, highly phosphorylated tau is more likely to be present in the cytosolic compartment of neurons, whereas reduced phosphate burden allows tau to bind to and stabilise the microtubule cytoskeleton. Highly phosphorylated forms of tau are deposited in the brain in a range of neurodegenerative disorders including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal lobar degeneration associated with Pick bodies. A key candidate kinase for both physiological and pathological tau phosphorylation is glycogen synthase kinase-3 (GSK-3). Multiple phosphorylation sites have been identified on tau exposed to GSK-3in vitroand in cells. In this review, we highlight recent data suggesting a role for GSK-3 activity on physiological tau function and on tau dysfunction in neurodegenerative disease.

scholarly journals The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

2019 ◽  
Author(s):  
Maritza Oñate ◽  
Alejandra Catenaccio ◽  
Natalia Salvadores ◽  
Cristian Saquel ◽  
Alexis Martinez ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Axonal Degeneration ◽  
Neuronal Loss ◽  
Postmortem Brain ◽  
Death Process ◽  
Early Event ◽  
Genetic Ablation ◽  
Postmortem Brain Tissue

AbstractParkinson’s disease (PD) is the second most common neurodegenerative condition, characterized by motor impairment due to the progressive degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine release in the striatum. Accumulating evidence suggest that degeneration of axons is an early event in the disease, involving destruction programs that are independent of the survival of the cell soma. Necroptosis, a programmed cell death process, is emerging as a mediator of neuronal loss in models of neurodegenerative diseases. Here, we demonstrate activation of necroptosis in postmortem brain tissue from PD patients and in a toxin-based mouse model of the disease. Inhibition of key components of the necroptotic pathway resulted in a significant delay of 6-hydroxydopamine dependent axonal degeneration of dopaminergic and cortical neurons in vitro. Genetic ablation of necroptosis mediators MLKL and RIPK3, as well as pharmacological inhibition of RIPK1 in vivo, decreased dopaminergic neuron degeneration, improving motor performance. Together, these findings suggest that axonal degeneration in PD is mediated by the necroptosis machinery, a process here referred to as necroaxoptosis, a druggable pathway to target dopaminergic neuronal loss.

scholarly journals Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

2019 ◽  
Author(s):  
Lenora Higginbotham ◽  
Lingyan Ping ◽  
Eric B. Dammer ◽  
Duc M. Duong ◽  
Maotian Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Postmortem Brain ◽  
Csf Biomarkers ◽  
Amyloid Accumulation ◽  
Cerebrospinal Fluid Biomarkers ◽  
Novel Biomarkers ◽  
The Brain ◽  
Brain Tissues

AbstractAlzheimer’s disease (AD) features a complex web of pathological processes beyond amyloid accumulation and tau-mediated neuronal death. To meaningfully advance AD therapeutics, there is an urgent need for novel biomarkers that comprehensively reflect these disease mechanisms. Here we applied an integrative proteomics approach to identify cerebrospinal fluid (CSF) biomarkers linked to a diverse set of pathophysiological processes in the diseased brain. Using multiplex proteomics, we identified >3,500 proteins across 40 CSF samples from control and AD patients and >12,000 proteins across 48 postmortem brain tissues from control, asymptomatic AD (AsymAD), AD, and other neurodegenerative cases. Co-expression network analysis of the brain tissues resolved 44 protein modules, nearly half of which significantly correlated with AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain-linked fluid markers representing a variety of cortical functions. Neuron-enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial-enriched myelination and immunity panels were highly increased in both the brain and CSF. Using high-throughput proteomic analysis, proteins from these panels were validated in an independent CSF cohort of control, AsymAD, and AD samples. Remarkably, several validated markers were significantly altered in AsymAD CSF and appeared to stratify subpopulations within this cohort. Overall, these brain-linked CSF biomarker panels represent a promising step toward a physiologically comprehensive tool that could meaningfully enhance the prognostic and therapeutic management of AD.

scholarly journals All tangled up: Tau-dependent neurodegeneration

2010 ◽  
Vol 32 (2) ◽  
pp. 10-13
Author(s):  
Ceri Lyn-Adams ◽  
Kevin Moffat ◽  
Calum Sutherland ◽  
Bruno G. Frenguelli
Keyword(s):  
Neurodegenerative Diseases ◽  
Progressive Supranuclear Palsy ◽  
Neurofibrillary Tangles ◽  
Neuronal Loss ◽  
Corticobasal Degeneration ◽  
Chromosome 17 ◽  
Phosphorylated Tau ◽  
Brain Correlates ◽  
Severity Of Dementia ◽  
The Brain

Currently, there are 30 million people worldwide suffering from dementia. This number is predicted to rise to 100 million if effective treatments aren't developed rapidly. Alzheimer's disease (AD) is the most common form of dementia and is also the most prevalent of a group of neurodegenerative diseases known as tauopathies. Tauopathies are characterized by intraneuronal inclusions (pretangles) composed of aggregates of highly phosphorylated tau in the form of paired helical or straight filaments (PHFs), and neuronal loss. As the load of PHFs increases, they will aggregate and eventually form neurofibrillary tangles (NFTs) which fill the whole cell. The number of tau tangles present in the brain correlates well with the severity of dementia. Tau tangles are routinely found in AD, frontotemporal dementia linked to chromosome 17 with parkinsonism (FTDP-17), progressive supranuclear palsy, Pick's disease, corticobasal degeneration, head trauma and Down's syndrome to name but a few.

scholarly journals Induced Expression of kir6.2 in A1 Astrocytes Propagates Inflammatory Neurodegeneration via Drp1-dependent Mitochondrial Fission

2021 ◽  
Vol 11 ◽  
Author(s):  
Nanshan Song ◽  
Hong Zhu ◽  
Rong Xu ◽  
Jiaqi Liu ◽  
Yinquan Fang ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Mitochondrial Fission ◽  
Neuronal Loss ◽  
Mitochondrial Fragmentation ◽  
Abnormal Response ◽  
Inflammatory Stimuli ◽  
Inflammatory Processes ◽  
The Brain ◽  
Intensive Control

Glia-mediated inflammatory processes are crucial in the pathogenesis of Parkinson’s disease (PD). As the most abundant cells of the brain and active participants in neuroinflammatory responses, astrocytes largely propagate inflammatory signals and amplify neuronal loss. Hence, intensive control of astrocytic activation is necessary to prevent neurodegeneration. In this study, we report that the astrocytic kir6.2, as a abnormal response after inflammatory stimuli, promotes the reactivity of A1 neurotoxic astrocytes. Using kir6.2 knockout (KO) mice, we find reversal effects of kir6.2 deficiency on A1-like astrocyte activation and death of dopaminergic neurons in lipopolysaccharide (LPS)-induced mouse models for PD. Further in vitro experiments show that aberrant kir6.2 expression induced by inflammatory irritants in astrocytes mediates the dynamin-related protein 1 (Drp1)-dependent excessive mitochondrial fragmentation and results in mitochondrial malfunctions. By deleting kir6.2, astrocytic activation is reduced and astrocytes-derived neuronal injury is prevented. We therefore conclude that astrocytic kir6.2 can potentially elucidate the pathology of PD and promote the development of therapeutic strategies for PD.

scholarly journals Influence of Metal Ions on Microtubules as a Possible Mechanism of Pathogenesis of Alzheimer′s Disease

2018 ◽  
Vol 1 (3) ◽  
pp. e00050
Author(s):  
P.N. Shevtsov ◽  
E.F. Shevtsova ◽  
S.O. Bachurin
Keyword(s):  
Metal Ions ◽  
Inferior Olive ◽  
Postmortem Brain ◽  
Control Group ◽  
Destructive Effect ◽  
Aluminum Ions ◽  
Associated Proteins ◽  
The Brain

The article provides an overview of our own results of comparative study of influence of ions of iron, zinc and aluminium on the structure of microtubules from tubulin and microtubules associated proteins of rat brain with data on the structure of microtubules from tubulin and microtubules associated proteins from the brain of patients with Alzheimer′s disease (AD). A significant decrease in the amount of soluble tubulin was found in the postmortem brain of AD patients in comparison with the control group in the hippocampus, frontal cortex and substantia nigra, but not in the inferior olive. In vitro polymerization of tubulin and microtubules associated proteins from the brain of AD patients and electron micrographs of microtubules were obtained. The assembly of microtubules from brains of AD patients is disrupted, resulting in defective structures. On the other hand, the study of the influence of Al3+, Fe3+, Zn2+ on the microtubules from rat brains tubulin and microtubules associated proteins assembly and structure has shown that all studied metals are able to reduce the amount of microtubules and induce the assembly of anomal structures. According to the degree of the destructive effect on the microtubules and, accordingly, the possible significance in the pathogenesis of Alzheimer disease, metal ions can be arranged in the following sequence Al3+ > Zn2+ > Fe3+. Moreover, phosphorylation of tubulin and microtubules associated proteins in the presence of aluminum ions to the greatest extent reflects the phosphorylation of these proteins at AD. Comparison of data on the structure of microtubules after their assembly from brains of AD patients tubulin and microtubules associated proteins from brains of AD patients, and from the brain of rats, but in the presence of metal ions, confirm the conclusion about the possible role of the metals in the AD etiopathogenesis.

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