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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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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 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.
Keywords: frontotemporal dementia, amyotrophic lateral sclerosis, TDP-43, parvalbumin, magnetic resonance imaging
College: Faculty of Medicine, Health and Life Sciences
Funders: 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.
Issue: 2

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