LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease
Abstract It has become evident that Alzheimer’s Disease (AD) is not only linked to its hallmark lesions—amyloid plaques and neurofibrillary tangles (NFTs)—but also to other co-occurring pathologies. This may lead to synergistic effects of the respective cellular and molecular players, resulting in n...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-022-01432-6 |
| _version_ | 1798004418843508736 |
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| author | Marta J. Koper Sandra O. Tomé Klara Gawor Annelies Belet Evelien Van Schoor Jolien Schaeverbeke Rik Vandenberghe Mathieu Vandenbulcke Estifanos Ghebremedhin Markus Otto Christine A. F. von Arnim Sriram Balusu Matthew B. Blaschko Bart De Strooper Dietmar Rudolf Thal |
| author_facet | Marta J. Koper Sandra O. Tomé Klara Gawor Annelies Belet Evelien Van Schoor Jolien Schaeverbeke Rik Vandenberghe Mathieu Vandenbulcke Estifanos Ghebremedhin Markus Otto Christine A. F. von Arnim Sriram Balusu Matthew B. Blaschko Bart De Strooper Dietmar Rudolf Thal |
| author_sort | Marta J. Koper |
| collection | DOAJ |
| description | Abstract It has become evident that Alzheimer’s Disease (AD) is not only linked to its hallmark lesions—amyloid plaques and neurofibrillary tangles (NFTs)—but also to other co-occurring pathologies. This may lead to synergistic effects of the respective cellular and molecular players, resulting in neuronal death. One of these co-pathologies is the accumulation of phosphorylated transactive-response DNA binding protein 43 (pTDP-43) as neuronal cytoplasmic inclusions, currently considered to represent limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), in up to 70% of symptomatic AD cases. Granulovacuolar degeneration (GVD) is another AD co-pathology, which also contains TDP-43 and other AD-related proteins. Recently, we found that all proteins required for necroptosis execution, a previously defined programmed form of neuronal cell death, are present in GVD, such as the phosphorylated necroptosis executioner mixed-lineage kinase domain-like protein (pMLKL). Accordingly, this protein is a reliable marker for GVD lesions, similar to other known GVD proteins. Importantly, it is not yet known whether the presence of LATE-NC in symptomatic AD cases is associated with necroptosis pathway activation, presumably contributing to neuron loss by cell death execution. In this study, we investigated the impact of LATE-NC on the severity of necroptosis-associated GVD lesions, phosphorylated tau (pTau) pathology and neuronal density. First, we used 230 human post-mortem cases, including 82 controls without AD neuropathological changes (non-ADNC), 81 non-demented cases with ADNC, i.e.: pathologically-defined preclinical AD (p-preAD) and 67 demented cases with ADNC. We found that Braak NFT stage and LATE-NC stage were good predictors for GVD expansion and neuronal loss in the hippocampal CA1 region. Further, we compared the impact of TDP-43 accumulation on hippocampal expression of pMLKL-positive GVD, pTau as well as on neuronal density in a subset of nine non-ADNC controls, ten symptomatic AD cases with (ADTDP+) and eight without LATE-NC (ADTDP−). Here, we observed increased levels of pMLKL-positive, GVD-exhibiting neurons in ADTDP+ cases, compared to ADTDP− and controls, which was accompanied by augmented pTau pathology. Neuronal loss in the CA1 region was increased in ADTDP+ compared to ADTDP− cases. These data suggest that co-morbid LATE-NC in AD impacts not only pTau pathology but also GVD-mediated necroptosis pathway activation, which results in an accelerated neuronal demise. This further highlights the cumulative and synergistic effects of comorbid pathologies leading to neuronal loss in AD. Accordingly, protection against necroptotic neuronal death appears to be a promising therapeutic option for AD and LATE. |
| first_indexed | 2024-04-11T12:24:27Z |
| format | Article |
| id | doaj.art-29e354dc5df743a1a8dfb1b935ec35c6 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-11T12:24:27Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-29e354dc5df743a1a8dfb1b935ec35c62022-12-22T04:24:00ZengBMCActa Neuropathologica Communications2051-59602022-09-0110111610.1186/s40478-022-01432-6LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s diseaseMarta J. Koper0Sandra O. Tomé1Klara Gawor2Annelies Belet3Evelien Van Schoor4Jolien Schaeverbeke5Rik Vandenberghe6Mathieu Vandenbulcke7Estifanos Ghebremedhin8Markus Otto9Christine A. F. von Arnim10Sriram Balusu11Matthew B. Blaschko12Bart De Strooper13Dietmar Rudolf Thal14Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenLaboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute (LBI), KU LeuvenLaboratory for Translational Neuropsychiatry, Department of Neuroscience, Leuven Brain Institute (LBI), KU LeuvenInstitute of Anatomy – Anatomy I, Johann Wolfgang Goethe UniversityDepartment of Neurology, Ulm UniversityDepartment of Neurology, Ulm UniversityLaboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU LeuvenDepartment of Electronics, Center for Processing Speech and Images, KU LeuvenLaboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU LeuvenLaboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU LeuvenAbstract It has become evident that Alzheimer’s Disease (AD) is not only linked to its hallmark lesions—amyloid plaques and neurofibrillary tangles (NFTs)—but also to other co-occurring pathologies. This may lead to synergistic effects of the respective cellular and molecular players, resulting in neuronal death. One of these co-pathologies is the accumulation of phosphorylated transactive-response DNA binding protein 43 (pTDP-43) as neuronal cytoplasmic inclusions, currently considered to represent limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), in up to 70% of symptomatic AD cases. Granulovacuolar degeneration (GVD) is another AD co-pathology, which also contains TDP-43 and other AD-related proteins. Recently, we found that all proteins required for necroptosis execution, a previously defined programmed form of neuronal cell death, are present in GVD, such as the phosphorylated necroptosis executioner mixed-lineage kinase domain-like protein (pMLKL). Accordingly, this protein is a reliable marker for GVD lesions, similar to other known GVD proteins. Importantly, it is not yet known whether the presence of LATE-NC in symptomatic AD cases is associated with necroptosis pathway activation, presumably contributing to neuron loss by cell death execution. In this study, we investigated the impact of LATE-NC on the severity of necroptosis-associated GVD lesions, phosphorylated tau (pTau) pathology and neuronal density. First, we used 230 human post-mortem cases, including 82 controls without AD neuropathological changes (non-ADNC), 81 non-demented cases with ADNC, i.e.: pathologically-defined preclinical AD (p-preAD) and 67 demented cases with ADNC. We found that Braak NFT stage and LATE-NC stage were good predictors for GVD expansion and neuronal loss in the hippocampal CA1 region. Further, we compared the impact of TDP-43 accumulation on hippocampal expression of pMLKL-positive GVD, pTau as well as on neuronal density in a subset of nine non-ADNC controls, ten symptomatic AD cases with (ADTDP+) and eight without LATE-NC (ADTDP−). Here, we observed increased levels of pMLKL-positive, GVD-exhibiting neurons in ADTDP+ cases, compared to ADTDP− and controls, which was accompanied by augmented pTau pathology. Neuronal loss in the CA1 region was increased in ADTDP+ compared to ADTDP− cases. These data suggest that co-morbid LATE-NC in AD impacts not only pTau pathology but also GVD-mediated necroptosis pathway activation, which results in an accelerated neuronal demise. This further highlights the cumulative and synergistic effects of comorbid pathologies leading to neuronal loss in AD. Accordingly, protection against necroptotic neuronal death appears to be a promising therapeutic option for AD and LATE.https://doi.org/10.1186/s40478-022-01432-6Granulovacuolar degenerationLATE-NCTDP-43NecroptosisCell deathpMLKL |
| spellingShingle | Marta J. Koper Sandra O. Tomé Klara Gawor Annelies Belet Evelien Van Schoor Jolien Schaeverbeke Rik Vandenberghe Mathieu Vandenbulcke Estifanos Ghebremedhin Markus Otto Christine A. F. von Arnim Sriram Balusu Matthew B. Blaschko Bart De Strooper Dietmar Rudolf Thal LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease Acta Neuropathologica Communications Granulovacuolar degeneration LATE-NC TDP-43 Necroptosis Cell death pMLKL |
| title | LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease |
| title_full | LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease |
| title_fullStr | LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease |
| title_full_unstemmed | LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease |
| title_short | LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease |
| title_sort | late nc aggravates gvd mediated necroptosis in alzheimer s disease |
| topic | Granulovacuolar degeneration LATE-NC TDP-43 Necroptosis Cell death pMLKL |
| url | https://doi.org/10.1186/s40478-022-01432-6 |
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