학술논문
Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration.
Document Type
Academic Journal
Author
Yousef A; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Robinson JL; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Irwin DJ; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Byrne MD; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Kwong LK; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Lee EB; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Xu Y; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Xie SX; Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Rennert L; Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Suh E; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Van Deerlin VM; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Grossman M; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Lee VM; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Trojanowski JQ; Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. trojanow@upenn.edu.
Source
Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE
Subject
Language
English
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.