Koper, Marta J;
Tome, Sandra O;
Gawor, Klara;
Belet, Annelies;
Van Schoor, Evelien;
Schaeverbeke, Jolien;
Vandenberghe, Rik;
... Thal, Dietmar Rudolf; + view all
(2022)
LATE-NC aggravates GVD-mediated necroptosis in Alzheimer's disease.
Acta Neuropathologica Communications
, 10
, Article 128. 10.1186/s40478-022-01432-6.
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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.
| Type: | Article |
|---|---|
| Title: | LATE-NC aggravates GVD-mediated necroptosis in Alzheimer's disease |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s40478-022-01432-6 |
| Publisher version: | https://doi.org/10.1186/s40478-022-01432-6 |
| Language: | English |
| Additional information: | © The Author(s) 2022.This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Granulovacuolar degeneration, LATE-NC, TDP-43, Necroptosis, Cell death, pMLKL, pTau, Protein aggregation, MIXED LINEAGE KINASE, DOMAIN-LIKE PROTEIN, GRANULOVACUOLAR DEGENERATION, NEUROFIBRILLARY TANGLES, TDP-43 PATHOLOGY, AMYLOID-BETA, HUMAN BRAIN, TAU, DEMENTIA, PHOSPHORYLATION |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10156084 |
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