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In model systems, these bodies have been shown to coordinate local nuclear protein synthesis with potential to seed diagnostic neuropathologies. Here we confirm the presence of nucleolar aggregates of amyloid nature in postmortem brain tissue from controls and patients with neurodegenerative pathologies and demonstrate the nucleolar sequestration of fibrillation-prone proteins associated with neurodegenerative diseases (A\u03b2, tau, \u03b1-synuclein, TDP-43, and FUS, but not prion or peptide repeats). We identified nucleolar bodies ranging from multiple small foci to a centralized, large amyloid aggresome, that appear to represent progressive stages of protein immobilization from liquid-like foci to the formation of nucleolar aggresomes. Neurons with nucleolar aggresomes were more vulnerable to neurodegeneration, decreasing in number with increasing duration of disease. Nucleolar aggresomes with phosphorylated tau correlated with increasing amounts of neuropathology, while phosphorylated TDP-43 in nucleolar aggresomes distinguished cases with limbic-predominant age-related TDP-43 encephalopathy. Nucleolar aggresomes containing \u03b1-synuclein occurred in a large proportion of aged controls with limited neuronal loss (potentially asserting neuroprotection). Other fibrillation-prone proteins were either absent (prion and peptide repeats) or found less commonly in nucleolar aggresomes (A\u03b2 and FUS), and amyloidogenic nuclear proteins not screened in this study may also occur in nucleolar aggresomes. Our data do not support the concept that proteins in aggresomes seed diagnostic neuropathologies as there were no associations between their presence in nucleoli aggresomes and their cytoplasmic or extracellular accumulation. Assessment of neurons with and without phosphorylated tau or \u03b1-synuclein aggresomes showed that phosphorylated tau ameliorated the increased DNA levels found in AD. Collectively, our observations establish that nucleolar sequestration of amyloidogenic proteins is a common molecular mechanism in the brain, representing a novel contribution to the understanding of nucleolar protein aggregation in the context of neuroprotection and neurodegeneration during brain aging.<\/jats:p>","DOI":"10.1007\/s00401-025-02968-2","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T18:14:47Z","timestamp":1764785687000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Nucleolar aggregation of key neuropathological proteins in the postmortem neurodegenerative brain"],"prefix":"10.1007","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2182-2949","authenticated-orcid":false,"given":"Guinevere F.","family":"Lourenco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8041-8420","authenticated-orcid":false,"given":"Maria Elizabeth","family":"Torres-Pacheco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-2039","authenticated-orcid":false,"given":"YuHong","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-3132","authenticated-orcid":false,"given":"Hongyun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8474-8969","authenticated-orcid":false,"given":"Heather","family":"McCann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0399-3218","authenticated-orcid":false,"given":"Claire E.","family":"Shepherd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9407-8674","authenticated-orcid":false,"given":"Jillian J.","family":"Kril","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0422-8398","authenticated-orcid":false,"given":"Glenda M.","family":"Halliday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"key":"2968_CR1","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-e","volume":"72","author":"The Huntington's Disease Collaborative Research Group","year":"1993","unstructured":"The Huntington\u2019s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. 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YF has received research grant funding from the University of Sydney-Fudan University BISA Flagship Research Program. CES has received research grant funding from the Profield, Minderoo and Michael J Fox (MJFF-023825) Foundations, and is a member of the editorial board for Frontiers in Neurology. GMH has received research grant funding from the National Health and Medical Research Council of Australia (1095127, 1132524, 1176607, 1191407, 2034292), Aligning Science Across Parkinson\u2019s (ASAP-000497, ASAP-020505, ASAP-020529, ASAP-025184), Michael J Fox Foundation (MJFF-021120, MJFF-023703, MJFF-024074), and National Institutes of Health USA (5RO1NS109209-02, 1RO1NS123142-01A1), research support from the University of Sydney, Aligning Science Across Parkinson\u2019s, Gordon Conferences, and the International Parkinson\u2019s and Movement Disorders Society, and is a member of the editorial boards for Science Advances, Neurobiology of Disease, Neuropathology and Applied Neurobiology, Translational Neurodegeneration, Journal of Parkinson\u2019s Disease and Acta Neuropathologica.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All brains used in this study were collected by the Sydney Brain Bank following informed consent. The study was approved by the University of Sydney\u2019s Human Research Ethics Committee (2018\/HE000128).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"60"}}