Disease-specific neuropathological alterations of the locus coeruleus in Alzheimer's disease, Down syndrome, and Parkinson's disease

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  • dc.contributor.author Fructuoso, Marta
  • dc.contributor.author Vermeiren, Yannick
  • dc.contributor.author Boluda, Susana
  • dc.contributor.author Stimmer, Lev
  • dc.contributor.author Crans, René A. J.
  • dc.contributor.author Xicota Vila, Laura, 1987-
  • dc.contributor.author Eisel, Uli
  • dc.contributor.author Ortí Casañ, Natalia
  • dc.contributor.author Bun, Philippe
  • dc.contributor.author Duyckaerts, Charles
  • dc.contributor.author Delabar, Jean-Maurice
  • dc.contributor.author Strydom, Andre
  • dc.contributor.author Van Dam, Debby
  • dc.contributor.author Dierssen, Mara
  • dc.contributor.author De Deyn, Peter
  • dc.contributor.author Potier, Marie-Claude
  • dc.date.accessioned 2025-09-08T11:49:08Z
  • dc.date.available 2025-09-08T11:49:08Z
  • dc.date.issued 2025
  • dc.description.abstract Introduction: The locus coeruleus (LC), the brain's primary source of noradrenaline (NA), undergoes early neurodegeneration in Parkinson's disease (PD), Alzheimer's diseases (AD), and Down syndrome (DS); however, differences have not been examined in parallel. Methods: Post mortem brains (n = 67) from individuals with AD, DS-AD, and PD without and with dementia (PD-D) and controls were analyzed for amyloid beta (Aβ), phosphorylated tau (pTau), α-synuclein, endo-lysosomal alterations, biogenic amines, and selective biomarkers. Results: LC degeneration correlated with age, peaking in AD and PD-D, while NA and dopaminergic metabolites were significantly reduced only in PD-D. DS-AD, the youngest group, showed the highest Aβ and pTau levels but the least noradrenergic neuron loss. We demonstrated for the first time that endosomal alterations were present in AD, lysosomal changes were present in PD-D/DS-AD, and DYRK1A, a key protein from chromosome 21, was elevated only in DS-AD. Discussion: Loss of noradrenergic neurons may occur independently of amyloid and tau pathologies. Highlights: We provide the first analysis of neuropathological and biochemical features including biogenic amines of the LC in AD, DS, and PD. Loss of noradrenergic neurons was most severe in AD and PD. Only in DS, levels of DYRK1A - a kinase encoded on chromosome 21 and implicated in neurodegenerative processes - were elevated and negatively correlated to biogenic amine levels. Although individuals with DS having AD were the youngest group, they had the highest levels of amyloid and tau pathologies, but less noradrenergic neurons loss compared to other disease groups.
  • dc.description.sponsorship The authors thank Jerome-Lejeune Fondation, which awarded M.F. and R.A.J.C. the Sisley d'Ornano-Lejeune postdoctoral fellowship 2019 and 2021, respectively. R.A.J.C. was also supported by the Sello de Excelencia ISCIII-HEALTH (IHMC22/00026). The authors thank Neuro-CEB (France), The Neurobiobank of the Institute Born-Bunge (NBB-IBB; FAGG registration ID BB190113) (Antwerp, Belgium), University of Groningen Brain Bank (the Netherlands), Institute of Psychiatry Kings College brain bank (UK), and Cambridge Brain Bank (UK) biobanks. The authors also thank Escourolle Laboratory of the Neuropathology Department of Pitié-Salpetrière Hospital in Paris (France). The authors gratefully acknowledge the Histomics core facility of ICM and the NeurImag Imaging core facility, part of the IPNP, Inserm 1266 unit and Université Paris Cité, part of the GIS IBISA and the national infrastructure France BioImaging supported by the National Research Agency (ANR-10-INBS-04). This study was supported by a grant from Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche JPND ANR-17-JPCD-0003 HEROES (postdoctoral fellowship to M.F.), the Centre Of Excellence Neurodegenerative Diseases Agence Nationale de la Recherche COEN-0002 COEN-4024 and MRC MR/R024901/1, Institut National de la Santé et de la Recherche Médicale in collaboration with the Paris Brain Institute (ICM), Institut Hospitalo-Universitario-A ICM, and was supported with funding from the Investissement d'Avenir (ANR-10-AIHU-06)). Part of the experiments were funded by the Agencia Estatal de Investigación (PID2022-141900OB-I00 INTO-DS, AC170006 to, ZonMW Grant 733051072). The CIBER of Rare Diseases is an initiative of the ISCIII. The authors acknowledge the support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI /10.13039/501100011033), the Generalitat de Catalunya through the CERCA program and to the EMBL partnership.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Fructuoso M, Vermeiren Y, Boluda S, Stimmer L, Crans RAJ, Xicota L, et al. Disease-specific neuropathological alterations of the locus coeruleus in Alzheimer's disease, Down syndrome, and Parkinson's disease. Alzheimers Dement. 2025 Jun;21(6):e70262. DOI: 10.1002/alz.70262
  • dc.identifier.doi http://dx.doi.org/10.1002/alz.70262
  • dc.identifier.issn 1552-5260
  • dc.identifier.uri http://hdl.handle.net/10230/71151
  • dc.language.iso eng
  • dc.publisher Wiley
  • dc.relation.ispartof Alzheimers Dement. 2025 Jun;21(6):e70262
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-141900OB-I00
  • dc.rights © 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword DYRK1A
  • dc.subject.keyword Endo‐lysosomal pathway
  • dc.subject.keyword Locus coeruleus
  • dc.subject.keyword Neurodegenerative diseases
  • dc.title Disease-specific neuropathological alterations of the locus coeruleus in Alzheimer's disease, Down syndrome, and Parkinson's disease
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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