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MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia

Ziqiang Lin, Eugene Kim, Mohi Ahmed, Han HAN, Camilla Simmons, Yushi Redhead, Jack Bartlett, Luis Emiliano Pena Altamira, Isobel Callaghan, Matthew A White, Nisha Singh, Stephen Sawiak, Tara Spires-Jones, Anthony C Vernon, Michael P Coleman, Jeremy Green, Christopher Henstridge, Jeffrey Davies Orcid Logo, Diana Cash, Jemeen Sreedharan

Brain Communications, Volume: 3, Issue: 2

Swansea University Authors: Han HAN, Jeffrey Davies Orcid Logo

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DOI (Published version): 10.1093/braincomms/fcab114

Abstract

Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selec...

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Published in: Brain Communications
ISSN: 2632-1297
Published: Oxford University Press (OUP) 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa57779
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Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. 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Sreedharan gratefully acknowledges support from the Motor Neuron Disease Association, the Medical Research Council UK (MR/K010611/1), the Lady Edith Wolfson Fellowship Fund, the van Geest Foundation, the Rosetrees Trust (M799), Alzheimer&#x2019;s Research UK (ARUK-PG2018B-008), and the Psychiatry Research Trust. M.P.C is supported by the van Geest Foundation. We gratefully acknowledge the Chinese Scholarship Council for supporting Ziqiang Lin during this study. 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spelling 2021-11-25T12:06:56.7702706 v2 57779 2021-09-06 MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia d38192914eb35bcb829963df26c22c52 Han HAN Han HAN true false 2cb3d1d96a7870a84d2f758e865172e6 0000-0002-4234-0033 Jeffrey Davies Jeffrey Davies true false 2021-09-06 MEDS Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice. Journal Article Brain Communications 3 2 Oxford University Press (OUP) 2632-1297 frontotemporal dementia, amyotrophic lateral sclerosis, TDP-43, parvalbumin, magnetic resonance imaging 27 5 2021 2021-05-27 10.1093/braincomms/fcab114 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University J. Sreedharan gratefully acknowledges support from the Motor Neuron Disease Association, the Medical Research Council UK (MR/K010611/1), the Lady Edith Wolfson Fellowship Fund, the van Geest Foundation, the Rosetrees Trust (M799), Alzheimer’s Research UK (ARUK-PG2018B-008), and the Psychiatry Research Trust. M.P.C is supported by the van Geest Foundation. We gratefully acknowledge the Chinese Scholarship Council for supporting Ziqiang Lin during this study. This work was supported by the Alzheimer’s Research UK King’s College London Network Centre. 2021-11-25T12:06:56.7702706 2021-09-06T15:33:58.1918335 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Ziqiang Lin 1 Eugene Kim 2 Mohi Ahmed 3 Han HAN 4 Camilla Simmons 5 Yushi Redhead 6 Jack Bartlett 7 Luis Emiliano Pena Altamira 8 Isobel Callaghan 9 Matthew A White 10 Nisha Singh 11 Stephen Sawiak 12 Tara Spires-Jones 13 Anthony C Vernon 14 Michael P Coleman 15 Jeremy Green 16 Christopher Henstridge 17 Jeffrey Davies 0000-0002-4234-0033 18 Diana Cash 19 Jemeen Sreedharan 20 57779__21089__93c6e67cf3544b0cbb23b99548048493.pdf 57779.pdf 2021-10-04T17:02:07.3359821 Output 3778304 application/pdf Version of Record true ©The Author(s) (2021). This is an Open Access article distributed under the terms of the Creative Commons Attribution License true eng http://creativecommons.org/licenses/by/4.0/
title MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia
spellingShingle MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia
Han HAN
Jeffrey Davies
title_short MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia
title_full MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia
title_fullStr MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia
title_full_unstemmed MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia
title_sort MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia
author_id_str_mv d38192914eb35bcb829963df26c22c52
2cb3d1d96a7870a84d2f758e865172e6
author_id_fullname_str_mv d38192914eb35bcb829963df26c22c52_***_Han HAN
2cb3d1d96a7870a84d2f758e865172e6_***_Jeffrey Davies
author Han HAN
Jeffrey Davies
author2 Ziqiang Lin
Eugene Kim
Mohi Ahmed
Han HAN
Camilla Simmons
Yushi Redhead
Jack Bartlett
Luis Emiliano Pena Altamira
Isobel Callaghan
Matthew A White
Nisha Singh
Stephen Sawiak
Tara Spires-Jones
Anthony C Vernon
Michael P Coleman
Jeremy Green
Christopher Henstridge
Jeffrey Davies
Diana Cash
Jemeen Sreedharan
format Journal article
container_title Brain Communications
container_volume 3
container_issue 2
publishDate 2021
institution Swansea University
issn 2632-1297
doi_str_mv 10.1093/braincomms/fcab114
publisher Oxford University Press (OUP)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.
published_date 2021-05-27T14:12:45Z
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