Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration
Abstract Background Microglial dysfunction is implicated in frontotemporal lobar degeneration (FTLD). Although studies have reported excessive microglial activation or senescence (dystrophy) in Alzheimer’s disease (AD), few have explored this in FTLD. We examined regional patterns of microglial burd...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-08-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01907-0 |
| _version_ | 1818294458066665472 |
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| author | Ione O. C. Woollacott Christina E. Toomey Catherine Strand Robert Courtney Bridget C. Benson Jonathan D. Rohrer Tammaryn Lashley |
| author_facet | Ione O. C. Woollacott Christina E. Toomey Catherine Strand Robert Courtney Bridget C. Benson Jonathan D. Rohrer Tammaryn Lashley |
| author_sort | Ione O. C. Woollacott |
| collection | DOAJ |
| description | Abstract Background Microglial dysfunction is implicated in frontotemporal lobar degeneration (FTLD). Although studies have reported excessive microglial activation or senescence (dystrophy) in Alzheimer’s disease (AD), few have explored this in FTLD. We examined regional patterns of microglial burden, activation and dystrophy in sporadic and genetic FTLD, sporadic AD and controls. Methods Immunohistochemistry was performed in frontal and temporal grey and white matter from 50 pathologically confirmed FTLD cases (31 sporadic, 19 genetic: 20 FTLD-tau, 26 FTLD-TDP, four FTLD-FUS), five AD cases and five controls, using markers to detect phagocytic (CD68-positive) and antigen-presenting (CR3/43-positive) microglia, and microglia in general (Iba1-positive). Microglial burden and activation (morphology) were assessed quantitatively for each microglial phenotype. Iba1-positive microglia were assessed semi-quantitatively for dystrophy severity and qualitatively for rod-shaped and hypertrophic morphology. Microglia were compared in each region between FTLD, AD and controls, and between different pathological subtypes of FTLD, including its main subtypes (FTLD-tau, FTLD-TDP, FTLD-FUS), and subtypes of FTLD-tau, FTLD-TDP and genetic FTLD. Microglia were also compared between grey and white matter within each lobe for each group. Results There was a higher burden of phagocytic and antigen-presenting microglia in FTLD and AD cases than controls, but activation was often not increased. Burden was generally higher in white matter than grey matter, but activation was greater in grey matter. However, microglia varied regionally according to FTLD subtype and disease mechanism. Dystrophy was more severe in FTLD and AD than controls, and more severe in white than grey matter, but this also varied regionally and was particularly extensive in FTLD due to progranulin (GRN) mutations. Presence of rod-shaped and hypertrophic microglia also varied by FTLD subtype. Conclusions This study demonstrates regionally variable microglial involvement in FTLD and links this to underlying disease mechanisms. This supports investigation of microglial dysfunction in disease models and consideration of anti-senescence therapies in clinical trials. |
| first_indexed | 2024-12-13T03:32:04Z |
| format | Article |
| id | doaj.art-4dcb6a68b8a84a2297d9a5a1dbbed721 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-13T03:32:04Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-4dcb6a68b8a84a2297d9a5a1dbbed7212022-12-22T00:01:08ZengBMCJournal of Neuroinflammation1742-20942020-08-0117112710.1186/s12974-020-01907-0Microglial burden, activation and dystrophy patterns in frontotemporal lobar degenerationIone O. C. Woollacott0Christina E. Toomey1Catherine Strand2Robert Courtney3Bridget C. Benson4Jonathan D. Rohrer5Tammaryn Lashley6Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of NeurologyQueen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of NeurologyQueen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of NeurologyQueen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of NeurologyQueen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of NeurologyDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of NeurologyQueen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of NeurologyAbstract Background Microglial dysfunction is implicated in frontotemporal lobar degeneration (FTLD). Although studies have reported excessive microglial activation or senescence (dystrophy) in Alzheimer’s disease (AD), few have explored this in FTLD. We examined regional patterns of microglial burden, activation and dystrophy in sporadic and genetic FTLD, sporadic AD and controls. Methods Immunohistochemistry was performed in frontal and temporal grey and white matter from 50 pathologically confirmed FTLD cases (31 sporadic, 19 genetic: 20 FTLD-tau, 26 FTLD-TDP, four FTLD-FUS), five AD cases and five controls, using markers to detect phagocytic (CD68-positive) and antigen-presenting (CR3/43-positive) microglia, and microglia in general (Iba1-positive). Microglial burden and activation (morphology) were assessed quantitatively for each microglial phenotype. Iba1-positive microglia were assessed semi-quantitatively for dystrophy severity and qualitatively for rod-shaped and hypertrophic morphology. Microglia were compared in each region between FTLD, AD and controls, and between different pathological subtypes of FTLD, including its main subtypes (FTLD-tau, FTLD-TDP, FTLD-FUS), and subtypes of FTLD-tau, FTLD-TDP and genetic FTLD. Microglia were also compared between grey and white matter within each lobe for each group. Results There was a higher burden of phagocytic and antigen-presenting microglia in FTLD and AD cases than controls, but activation was often not increased. Burden was generally higher in white matter than grey matter, but activation was greater in grey matter. However, microglia varied regionally according to FTLD subtype and disease mechanism. Dystrophy was more severe in FTLD and AD than controls, and more severe in white than grey matter, but this also varied regionally and was particularly extensive in FTLD due to progranulin (GRN) mutations. Presence of rod-shaped and hypertrophic microglia also varied by FTLD subtype. Conclusions This study demonstrates regionally variable microglial involvement in FTLD and links this to underlying disease mechanisms. This supports investigation of microglial dysfunction in disease models and consideration of anti-senescence therapies in clinical trials.http://link.springer.com/article/10.1186/s12974-020-01907-0Frontotemporal dementiaFrontotemporal lobar degenerationMicrogliaDystrophyNeuroinflammationProgranulin |
| spellingShingle | Ione O. C. Woollacott Christina E. Toomey Catherine Strand Robert Courtney Bridget C. Benson Jonathan D. Rohrer Tammaryn Lashley Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration Journal of Neuroinflammation Frontotemporal dementia Frontotemporal lobar degeneration Microglia Dystrophy Neuroinflammation Progranulin |
| title | Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration |
| title_full | Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration |
| title_fullStr | Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration |
| title_full_unstemmed | Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration |
| title_short | Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration |
| title_sort | microglial burden activation and dystrophy patterns in frontotemporal lobar degeneration |
| topic | Frontotemporal dementia Frontotemporal lobar degeneration Microglia Dystrophy Neuroinflammation Progranulin |
| url | http://link.springer.com/article/10.1186/s12974-020-01907-0 |
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