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Your search keyword '"Mckenzie, Chris-Anne"' showing total 4 results
Start Over Author "Mckenzie, Chris-Anne" Topic aging
4 results on '"Mckenzie, Chris-Anne"'

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

Author

Fan LM, Geng L, Cahill-Smith S, Liu F, Douglas G, Mckenzie CA, Smith C, Brooks G, Channon KM, and Li JM

Subjects
Adult, Aged, Aged, 80 and over, Aging genetics, Aging pathology, Animals, Capillaries pathology, Endothelium, Vascular pathology, Female, Humans, Male, Mice, Mice, Knockout, Middle Aged, NADPH Oxidase 2 genetics, Neurons, Oxidation-Reduction, Aging metabolism, Brain blood supply, Brain enzymology, Brain pathology, Capillaries enzymology, Endothelial Cells enzymology, Endothelial Cells pathology, Endothelium, Vascular enzymology, NADPH Oxidase 2 metabolism, Reactive Oxygen Species metabolism, Signal Transduction
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 γH2AX; 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.

Published
2019
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2. Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse.

Author

Henstridge CM, Jackson RJ, Kim JM, Herrmann AG, Wright AK, Harris SE, Bastin ME, Starr JM, Wardlaw J, Gillingwater TH, Smith C, McKenzie CA, Cox SR, Deary IJ, and Spires-Jones TL

Subjects
Aged, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Brain metabolism, Cohort Studies, Female, Histones metabolism, Humans, Image Processing, Computer-Assisted, Male, Membrane Proteins metabolism, Microglia pathology, Middle Aged, Nerve Tissue Proteins metabolism, Neurons pathology, Neurons ultrastructure, Postmortem Changes, Synapses metabolism, Synapses ultrastructure, Aging pathology, Brain pathology, Cognition, Synapses pathology
Abstract

Introduction: Non-pathological, age-related cognitive decline varies markedly between individuals andplaces significant financial and emotional strain on people, their families and society as a whole.Understanding the differential age-related decline in brain function is critical not only for the development oftherapeutics to prolong cognitive health into old age, but also to gain insight into pathological ageing suchas Alzheimer's disease. The Lothian Birth Cohort of 1936 (LBC1936) comprises a rare group of people forwhom there are childhood cognitive test scores and longitudinal cognitive data during older age, detailedstructural brain MRI, genome-wide genotyping, and a multitude of other biological, psycho-social, andepidemiological data. Synaptic integrity is a strong indicator of cognitive health in the human brain;however, until recently, it was prohibitively difficult to perform detailed analyses of synaptic and axonalstructure in human tissue sections. We have adapted a novel method of tissue preparation at autopsy toallow the study of human synapses from the LBC1936 cohort in unprecedented morphological andmolecular detail, using the high-resolution imaging techniques of array tomography and electronmicroscopy. This allows us to analyze the brain at sub-micron resolution to assess density, proteincomposition and health of synapses. Here we present data from the first donated LBC1936 brain andcompare our findings to Alzheimer's diseased tissue to highlight the differences between healthy andpathological brain ageing., Results: Our data indicates that compared to an Alzheimer's disease patient, the cognitively normalLBC1936 participant had a remarkable degree of preservation of synaptic structures. However,morphological and molecular markers of degeneration in areas of the brain associated with cognition(prefrontal cortex, anterior cingulate cortex, and superior temporal gyrus) were observed., Conclusions: Our novel post-mortem protocol facilitates high-resolution neuropathological analysis of the well-characterized LBC1936 cohort, extending phenotyping beyond cognition and in vivo imaging to nowinclude neuropathological changes, at the level of single synapses. This approach offers an unprecedentedopportunity to study synaptic and axonal integrity during ageing and how it contributes to differences in agerelatedcognitive change.

Published
2015
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3. 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

4. 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-Akanbi, Marzena, Santibanez-Koref, Mauro, Talbot, Kevin, Turner, Martin R, McKenzie, Chris-Anne, Troakes, Claire, Attems, Johannes, Smith, Colin, Al Sarraj, Safa, Morris, Christopher M, Ansorge, Olaf, Pickering-Brown, Stuart, Ironside, James W, and Chinnery, Patrick F

Subjects
Aged, 80 and over, Male, Aging, Brain Diseases, DNA Copy Number Variations, Brain, Sequence Analysis, DNA, Middle Aged, DNA, Mitochondrial, Polymorphism, Single Nucleotide, 3. Good health, Mitochondrial, Cohort Studies, Mutation, Humans, Point Mutation, Dementia, Exome, Female, Somatic, Neurodegeneration, 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.

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