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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\n                    <jats:italic>post-mortem<\/jats:italic>\n                    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 (AD\n                    <jats:sup>TDP+<\/jats:sup>\n                    ) and eight without LATE-NC (AD\n                    <jats:sup>TDP\u2212<\/jats:sup>\n                    ). Here, we observed increased levels of pMLKL-positive, GVD-exhibiting neurons in AD\n                    <jats:sup>TDP+<\/jats:sup>\n                    cases, compared to AD\n                    <jats:sup>TDP\u2212<\/jats:sup>\n                    and controls, which was accompanied by augmented pTau pathology. Neuronal loss in the CA1 region was increased in AD\n                    <jats:sup>TDP+<\/jats:sup>\n                    compared to AD\n                    <jats:sup>TDP\u2212<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1186\/s40478-022-01432-6","type":"journal-article","created":{"date-parts":[[2022,9,3]],"date-time":"2022-09-03T11:04:26Z","timestamp":1662203066000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["LATE-NC aggravates GVD-mediated necroptosis in Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"10","author":[{"given":"Marta J.","family":"Koper","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5253-0730","authenticated-orcid":false,"given":"Sandra O.","family":"Tom\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Gawor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"Belet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelien","family":"Van Schoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Schaeverbeke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Vandenberghe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Vandenbulcke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estifanos","family":"Ghebremedhin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Otto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A. 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Ethical approval for the use of cases was granted by the ethical committee of Ulm University (Germany) and UZ\/KU-Leuven ethical committee (Belgium). This study covering the retrospective analysis of samples and data was approved by the UZ\/KU-Leuven ethical committee (S-59295, S-65147) (Belgium).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable for this study, which did not use person\u2019s data. Only anonymized or pseudonymized data were processed.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MO served as consultant for Axon neuroscience and Fujirebio and gave invited talks for Roche and Fujirebio. CAFvA received honoraria from serving on the scientific advisory board of Nutricia GmbH (2014), Roche (2018) and Hong Kong University Research council (2014) and has received funding for travel and speaker honoraria from Nutricia GmbH (2014\u20132015), Lilly Deutschland GmbH (2013\u20132016), Desitin Arzneimittel GmbH (2014), Biogen (2016\u20132018), Roche (2017\u20132019) and Dr. Willmar Schwabe GmbH &Co. KG (2014\u20132019). BDS is or has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies. BDS is also a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna therapeutics. DRT received speaker honorary from Novartis Pharma AG (Switzerland) and Biogen (USA), travel reimbursement from GE-Healthcare (UK) and UCB (Belgium) and collaborated with Novartis Pharma AG (Switzerland), Probiodrug (Germany), GE-Healthcare (UK), and Janssen Pharmaceutical Companies (Belgium).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"128"}}