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2. Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature

Author

Fan, Lampson M., Geng, Li, Cahill-Smith, Sarah, Liu, Fangfei, Douglas, Gillian, Mckenzie, Chris-Anne, Smith, Colin, Brooks, Gavin, Channon, Keith M., and Li, Jian-Mei

Subjects
Brain -- Comparative analysis, Genetic engineering -- Comparative analysis, Neurophysiology -- Comparative analysis, Tumor proteins -- Comparative analysis, Angiotensin II -- Comparative analysis, Endothelium -- Comparative analysis, Brain damage -- Comparative analysis, Neurons -- Comparative analysis, Oxidative stress, Angiotensins, Health care industry
Abstract

Oxidative stress plays an important role in aging-related neurodegeneration. This study used littermates of WT and Nox2-knockout (Nox2KO) mice plus endothelial cell-specific human Nox2 overexpression-transgenic (HuNox2Tg) mice to investigate Nox2-derived ROS in brain aging. Compared with young WT mice (3-4 months), aging WT mice (20-22 months) had obvious metabolic disorders and loss of locomotor activity. Aging WT brains had high levels of angiotensin II (Ang II) and ROS production; activation of ERK1/2, p53, and [gamma]H2AX; and losses of capillaries and neurons. However, these abnormalities were markedly reduced in aging Nox2KO brains. HuNox2Tg brains at middle age (11-12 months) already had high levels of ROS production and activation of stress signaling pathways similar to those found in aging WT brains. The mechanism of Ang II-induced endothelial Nox2 activation in capillary damage was examined using primary brain microvascular endothelial cells. The clinical significance of Nox2-derived ROS in aging-related loss of cerebral capillaries and neurons was investigated using postmortem midbrain tissues of young (25-38 years) and elderly (61-85 years) adults. In conclusion, Nox2 activation is an important mechanism in aging-related cerebral capillary rarefaction and reduced brain function, with the possibility of a key role for endothelial cells., Introduction The brain is a highly metabolic organ requiring a consistent supply of oxygen and nutrients for normal function. Ensuring a sufficient oxygen and nutrition supply to the brain is [...]

Published
2019
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5. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies

Author

Colom-Cadena, Martí, Pegueroles, Jordi, Herrmann, Abigail G, Henstridge, Christopher M, Muñoz, Laia, Querol-Vilaseca, Marta, Martín-Paniello, Carla San, Luque-Cabecerans, Joan, Clarimon, Jordi, Belbin, Olivia, Núñez-Llaves, Raúl, Blesa, Rafael, Smith, Colin, McKenzie, Chris-Anne, Frosch, Matthew P, Roe, Allyson, Fortea, Juan, Andilla, Jordi, Loza-Alvarez, Pablo, Gelpi, Ellen, Hyman, Bradley T, Spires-Jones, Tara L, and Lleó, Alberto

Published
2017
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6. Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism

Author

MacAskill, Mark G., primary, Stadulyte, Agne, additional, Williams, Lewis, additional, Morgan, Timaeus E.F., additional, Sloan, Nikki L., additional, Alcaide-Corral, Carlos J., additional, Walton, Tashfeen, additional, Wimberley, Catriona, additional, McKenzie, Chris-Anne, additional, Spath, Nick, additional, Mungall, William, additional, BouHaidar, Ralph, additional, Dweck, Marc R., additional, Gray, Gillian A., additional, Newby, David E., additional, Lucatelli, Christophe, additional, Sutherland, Andrew, additional, Pimlott, Sally L., additional, and Tavares, Adriana A.S., additional

Published
2020
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7. Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer’s Disease

Author

Pickett, Eleanor K., primary, Herrmann, Abigail G., additional, McQueen, Jamie, additional, Abt, Kimberly, additional, Dando, Owen, additional, Tulloch, Jane, additional, Jain, Pooja, additional, Dunnett, Sophie, additional, Sohrabi, Sadaf, additional, Fjeldstad, Maria P., additional, Calkin, Will, additional, Murison, Leo, additional, Jackson, Rosemary J., additional, Tzioras, Makis, additional, Stevenson, Anna, additional, d’Orange, Marie, additional, Hooley, Monique, additional, Davies, Caitlin, additional, Colom-Cadena, Marti, additional, Anton-Fernandez, Alejandro, additional, King, Declan, additional, Oren, Iris, additional, Rose, Jamie, additional, McKenzie, Chris-Anne, additional, Allison, Elizabeth, additional, Smith, Colin, additional, Hardt, Oliver, additional, Henstridge, Christopher M., additional, Hardingham, Giles E., additional, and Spires-Jones, Tara L., additional

Published
2019
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8. Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism.

Author

MacAskill, Mark G., Stadulyte, Agne, Williams, Lewis, Morgan, Timaeus E. F., Sloan, Nikki L., Alcaide- Corral, Carlos J., Walton, Tashfeen, Wimberley, Catriona, McKenzie, Chris-Anne, Spath, Nick, Mungall, William, BouHaidar, Ralph, Dweck, Marc R., Gray, Gillian A., Newby, David E., Lucatelli, Christophe, Sutherland, Andrew, Pimlott, Sally L., and Tavares, Adriana A. S.

Published
2021
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9. Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains

Author

Wei, Wei, Keogh, Michael J, Wilson, Ian, Coxhead, Jonathan, Ryan, Sarah, Rollinson, Sara, Griffin, Helen, Kurzawa-Akinibi, Marzena, Santibanez Koref, Mauro, Talbot, Kevin, Turner, Martin J, McKenzie, Chris-Anne, Troakes, Claire, Attems, Johannes, Smith, Colin, Al-Sarraj, Safa, Morris, Christopher M, Ansorge, Olaf, Pickering-Brown, Stuart, Ironside, James, Chinnery, Patrick F, Chinnery, Patrick [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
Aged, 80 and over, Male, Aging, Brain Diseases, DNA Copy Number Variations, Research, Brain, Sequence Analysis, DNA, Middle Aged, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Mitochondrial, Cohort Studies, Mutation, Humans, Point Mutation, Dementia, Exome, Female, Somatic, Neurodegeneration, Letter to the Editor, Aged
Abstract

Mitochondria play a key role in common neurodegenerative diseases and contain their own genome: mtDNA. Common inherited polymorphic variants of mtDNA have been associated with several neurodegenerative diseases, and somatic deletions of mtDNA have been found in affected brain regions. However, there are conflicting reports describing the role of rare inherited variants and somatic point mutations in neurodegenerative disorders, and recent evidence also implicates mtDNA levels. To address these issues we studied 1363 post mortem human brains with a histopathological diagnosis of Parkinson’s disease (PD), Alzheimer’s disease (AD), Frontotemporal dementia – Amyotrophic Lateral Sclerosis (FTD-ALS), Creutzfeldt Jacob disease (CJD), and healthy controls. We obtained high-depth whole mitochondrial genome sequences using off target reads from whole exome sequencing to determine the association of mtDNA variation with the development and progression of disease, and to better understand the development of mtDNA mutations and copy number in the aging brain. With this approach, we found a surprisingly high frequency of heteroplasmic mtDNA variants in 32.3% of subjects. However, we found no evidence of an association between rare inherited variants of mtDNA or mtDNA heteroplasmy and disease. In contrast, we observed a reduction in the amount of mtDNA copy in both AD and CJD. Based on these findings, single nucleotide variants of mtDNA are unlikely to play a major role in the pathogenesis of these neurodegenerative diseases, but mtDNA levels merit further investigation. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0404-6) contains supplementary material, which is available to authorized users.

Published
2017

10. Quantification of macrophage-driven inflammation during myocardial infarction with 18F-LW223, a novel TSPO radiotracer with binding independent of the rs6971 human polymorphism.

Author

MacAskill, Mark G., Stadulyte, Agne, Williams, Lewis, Morgan, Timaeus E. F., Sloan, Nikki L., Alcaide-Corral, Carlos J., Walton, Tashfeen, Wimberley, Catriona, McKenzie, Chris-Anne, Spath, Nick, Mungall, William, BouHaidar, Ralph, Dweck, Marc R., Gray, Gillian A., Newby, David E., Lucatelli, Christophe, Sutherland, Andrew, Pimlott, Sally L., and Tavares, Adriana A. S.

Published
2020
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12. Erratum to: Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains

Author

Wei, Wei, primary, Keogh, Michael J., additional, Wilson, Ian, additional, Coxhead, Jonathan, additional, Ryan, Sarah, additional, Rollinson, Sara, additional, Griffin, Helen, additional, Kurzawa-Akanbi, Marzena, additional, Santibanez-Koref, Mauro, additional, Talbot, Kevin, additional, Turner, Martin R., additional, McKenzie, Chris-Anne, additional, Troakes, Claire, additional, Attems, Johannes, additional, Smith, Colin, additional, Al Sarraj, Safa, additional, Morris, Christopher M., additional, Ansorge, Olaf, additional, Pickering-Brown, Stuart, additional, Ironside, James W., additional, and Chinnery, Patrick F, additional

Published
2017
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13. Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains

Author

Wei, Wei, primary, Keogh, Michael J., additional, Wilson, Ian, additional, Coxhead, Jonathan, additional, Ryan, Sarah, additional, Rollinson, Sara, additional, Griffin, Helen, additional, Kurzawa-Akanbi, Marzena, additional, Santibanez-Koref, Mauro, additional, Talbot, Kevin, additional, Turner, Martin R., additional, McKenzie, Chris-Anne, additional, Troakes, Claire, additional, Attems, Johannes, additional, Smith, Colin, additional, Al Sarraj, Safa, additional, Morris, Christopher M., additional, Ansorge, Olaf, additional, Pickering-Brown, Stuart, additional, Ironside, James W., additional, and Chinnery, Patrick F, additional

Published
2017
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14. Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource

Author

Keogh, Michael J., primary, Wei, Wei, additional, Wilson, Ian, additional, Coxhead, Jon, additional, Ryan, Sarah, additional, Rollinson, Sara, additional, Griffin, Helen, additional, Kurzawa-Akanbi, Marzena, additional, Santibanez-Koref, Mauro, additional, Talbot, Kevin, additional, Turner, Martin R., additional, McKenzie, Chris-Anne, additional, Troakes, Claire, additional, Attems, Johannes, additional, Smith, Colin, additional, Al Sarraj, Safa, additional, Morris, Chris M., additional, Ansorge, Olaf, additional, Pickering-Brown, Stuart, additional, Ironside, James W., additional, and Chinnery, Patrick F., additional

Published
2016
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16. Erratum to: Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse

Author

Henstridge, Christopher M., primary, Jackson, Rosemary J., additional, Kim, JeeSoo M., additional, Herrmann, Abigail G., additional, Wright, Ann K., additional, Harris, Sarah E., additional, Bastin, Mark E., additional, Starr, John M., additional, Wardlaw, Joanna, additional, Gillingwater, Thomas H., additional, Smith, Colin, additional, McKenzie, Chris-Anne, additional, Cox, Simon R., additional, Deary, Ian J., additional, and Spires-Jones, Tara L., additional

Published
2015
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17. Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse

Author

Henstridge, Christopher M., primary, Jackson, Rosemary J., additional, Kim, JeeSoo M., additional, Herrmann, Abigail G., additional, Wright, Ann K., additional, Harris, Sarah E., additional, Bastin, Mark E., additional, Starr, John M., additional, Wardlaw, Joanna, additional, Gillingwater, Thomas H., additional, Smith, Colin, additional, McKenzie, Chris-Anne, additional, Cox, Simon R., additional, Deary, Ian J., additional, and Spires-Jones, Tara L., additional

Published
2015
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18. Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource

Author

Keogh, Michael J., Wei, Wei, Wilson, Ian, Coxhead, Jon, Ryan, Sarah, Rollinson, Sara, Griffin, Helen, Kurzawa-Akanbi, Marzena, Santibanez-Koref, Mauro, Talbot, Kevin, Turner, Martin R., McKenzie, Chris-Anne, Troakes, Claire, Attems, Johannes, Smith, Colin, Al Sarraj, Safa, Morris, Chris M., Ansorge, Olaf, Pickering-Brown, Stuart, Ironside, James W., and Chinnery, Patrick F.

Abstract

Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n= 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n= 252), Creutzfeldt-Jakob disease (CJD, n= 239), Parkinson's disease (PD, n= 39), dementia with Lewy bodies (DLB, n= 58), other neurodegenerative, vascular, or neurogenetic disorders (n= 266), and controls with no significant neuropathology (n= 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72repeat expansion detection; and APOEgenotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRNand DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPHthat were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies.

Published
2017
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19. Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18 F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism.

Author

MacAskill MG, Stadulyte A, Williams L, Morgan TEF, Sloan NL, Alcaide-Corral CJ, Walton T, Wimberley C, McKenzie CA, Spath N, Mungall W, BouHaidar R, Dweck MR, Gray GA, Newby DE, Lucatelli C, Sutherland A, Pimlott SL, and Tavares AAS

Subjects
Animals, Fluorine Radioisotopes analysis, Inflammation immunology, Macrophages cytology, Macrophages immunology, Male, Myocardial Infarction genetics, Myocardial Infarction metabolism, Radioactive Tracers, Rats, Sprague-Dawley, Receptors, GABA genetics, Rats, Macrophages metabolism, Myocardial Infarction diagnostic imaging, Myocardial Infarction immunology, Polymorphism, Single Nucleotide, Positron Emission Tomography Computed Tomography, Receptors, GABA metabolism
Abstract

Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18 F-LW223, are suitable for clinical translation; and validate whether 18 F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3 H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K 1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BP TC ). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18 F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5-24.5 μSv/MBq). 18 F-LW223 BP TC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm 3 /mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BP TC analysis. Conclusion: 18 F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Published
2021
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