Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration
Abstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is associated with the accumulation of pathological neuronal and glial intracytoplasmic inclusions as well as accompanying neuron loss. We explored if cortical neurons detected by NeuN decreased with increasing TDP-43 inclu...
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doaj-5847f68a2cf34cfe9bcd1e0ae715b6172020-11-24T22:17:11ZengBMCActa Neuropathologica Communications2051-59602017-09-015111510.1186/s40478-017-0471-3Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degenerationAhmed Yousef0John L. Robinson1David J. Irwin2Matthew D. Byrne3Linda K. Kwong4Edward B. Lee5Yan Xu6Sharon X. Xie7Lior Rennert8EunRan Suh9Vivianna M. Van Deerlin10Murray Grossman11Virginia M.-Y. Lee12John Q. Trojanowski13Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineDepartment of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of MedicineDepartment of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineCenter for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of MedicineAbstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is associated with the accumulation of pathological neuronal and glial intracytoplasmic inclusions as well as accompanying neuron loss. We explored if cortical neurons detected by NeuN decreased with increasing TDP-43 inclusion pathology in the postmortem brains of 63 patients with sporadic and familial FTLD-TDP. Semi-automated quantitative algorithms to quantify histology in tissue sections stained with antibodies specific for pathological or phosphorylated TDP-43 (pTDP-43) and NeuN were developed and validated in affected (cerebral cortex) and minimally affected (cerebellar cortex) brain regions of FTLD-TDP cases. Immunohistochemistry (IHC) for NeuN and other neuronal markers found numerous neurons lacking reactivity, suggesting NeuN may reflect neuron health rather than neuron loss in FTLD. We found three patterns of NeuN and pTDP-43 reactivity in our sample of cortical tissue representing three intracortical region-specific stages of FTLD-TDP progression: Group 1 showed low levels of pathological pTDP-43 and high levels NeuN, while Group 2 showed increased levels of pTDP-43, and Group 3 tissues were characterized by reduced staining for both pTDP-43 and NeuN. Comparison of non-C9orf72/GRN FTLD-TDP with cases linked to both GRN mutations and C9orf72 expansions showed a significantly increased frequency of Group 3 histopathology in the latter cases, suggesting more advanced cortical disease. Hence, we propose that IHC profiles of pTDP-43 and NeuN reflect the burden of pTDP-43 and its deleterious effects on neuron health.http://link.springer.com/article/10.1186/s40478-017-0471-3TDP-43C9orf72GRNFrontotemporal lobar degenerationNeuNNeurodegeneration |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ahmed Yousef John L. Robinson David J. Irwin Matthew D. Byrne Linda K. Kwong Edward B. Lee Yan Xu Sharon X. Xie Lior Rennert EunRan Suh Vivianna M. Van Deerlin Murray Grossman Virginia M.-Y. Lee John Q. Trojanowski |
spellingShingle |
Ahmed Yousef John L. Robinson David J. Irwin Matthew D. Byrne Linda K. Kwong Edward B. Lee Yan Xu Sharon X. Xie Lior Rennert EunRan Suh Vivianna M. Van Deerlin Murray Grossman Virginia M.-Y. Lee John Q. Trojanowski Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration Acta Neuropathologica Communications TDP-43 C9orf72 GRN Frontotemporal lobar degeneration NeuN Neurodegeneration |
author_facet |
Ahmed Yousef John L. Robinson David J. Irwin Matthew D. Byrne Linda K. Kwong Edward B. Lee Yan Xu Sharon X. Xie Lior Rennert EunRan Suh Vivianna M. Van Deerlin Murray Grossman Virginia M.-Y. Lee John Q. Trojanowski |
author_sort |
Ahmed Yousef |
title |
Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration |
title_short |
Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration |
title_full |
Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration |
title_fullStr |
Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration |
title_full_unstemmed |
Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration |
title_sort |
neuron loss and degeneration in the progression of tdp-43 in frontotemporal lobar degeneration |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2017-09-01 |
description |
Abstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is associated with the accumulation of pathological neuronal and glial intracytoplasmic inclusions as well as accompanying neuron loss. We explored if cortical neurons detected by NeuN decreased with increasing TDP-43 inclusion pathology in the postmortem brains of 63 patients with sporadic and familial FTLD-TDP. Semi-automated quantitative algorithms to quantify histology in tissue sections stained with antibodies specific for pathological or phosphorylated TDP-43 (pTDP-43) and NeuN were developed and validated in affected (cerebral cortex) and minimally affected (cerebellar cortex) brain regions of FTLD-TDP cases. Immunohistochemistry (IHC) for NeuN and other neuronal markers found numerous neurons lacking reactivity, suggesting NeuN may reflect neuron health rather than neuron loss in FTLD. We found three patterns of NeuN and pTDP-43 reactivity in our sample of cortical tissue representing three intracortical region-specific stages of FTLD-TDP progression: Group 1 showed low levels of pathological pTDP-43 and high levels NeuN, while Group 2 showed increased levels of pTDP-43, and Group 3 tissues were characterized by reduced staining for both pTDP-43 and NeuN. Comparison of non-C9orf72/GRN FTLD-TDP with cases linked to both GRN mutations and C9orf72 expansions showed a significantly increased frequency of Group 3 histopathology in the latter cases, suggesting more advanced cortical disease. Hence, we propose that IHC profiles of pTDP-43 and NeuN reflect the burden of pTDP-43 and its deleterious effects on neuron health. |
topic |
TDP-43 C9orf72 GRN Frontotemporal lobar degeneration NeuN Neurodegeneration |
url |
http://link.springer.com/article/10.1186/s40478-017-0471-3 |
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