Common pathogenic mechanisms in the hippocampus across neurodegenerative dementias: Alzheimer’s disease, Down syndrome, and Parkinson’s disease

Authors:
  • MFMarta Fructuoso
    Marta Fructuoso
  • KBKaren Bascón-Cardozo
    Karen Bascón-Cardozo
  • HRHatice Recaioglu
    Hatice Recaioglu
  • JSJesus Sotelo-Fonseca
    Jesus Sotelo-Fonseca
  • YVYannick Vermeiren
    Yannick Vermeiren
  • ASAndré Strydom
    André Strydom
  • DDDebby Van Dam
    Debby Van Dam
  • PDPeter P. De Deyn
    Peter P. De Deyn
  • BRBernardo Rodríguez-Martín
    Bernardo Rodríguez-Martín
  • MPMarie-Claude Potier
    Marie-Claude Potier
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Abstract
Extensive evidence suggests overlapping pathological mechanisms in the brain of individuals with Parkinson’s disease dementia, Down syndrome dementia, and Alzheimer’s disease. For these neurodegenerative dementias, we observed that the chronological age did not align with their biological age, which was determined based on hippocampal transcript levels (i.e., transcriptional age). Subsequently, we performed a transcriptomic analysis that corrected for the transcriptional age in the hippocampus of affected individuals, highlighting common underlying pathogenic mechanisms. There were 45 common differentially expressed genes (DEGs), whereas enriched functional terms were related to lysine N -methyltransferase activity and intermediate filament. Co-expression network analysis displayed a module that was significantly downregulated in the non-demented control group only. This module identified EHMT2 and LMNB2 as hub genes, which were also common DEGs. Overall, these findings uncover shared functional insights in the hippocampus, while specifically highlighting EHMT2 and LMNB2 as potential universal biomarkers or disease-altered targets across neurodegenerative dementias.
Funding Information
  • Jérôme-Lejeune Fondation (15_PDC-2021)
  • Jérôme-Lejeune Fondation (12_PDC-2019)
  • ISCIII Sello Excelencia ISCIII-Health (IHMC22/00026)
  • Ministerio de Ciencia Innovacion y Universidades (RTC2019-007230-1, RTC2019-007329-1, and CPP2022-009659)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • Joint Program Neurodegenerative Diseases Agence Nationale de la Recherche (JPND ANR-17-JPCD-0003 HEROES and JPND HEROES AC170006)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • FP7 Coherent Development of Research Policies (848077 and 899986)
  • Medical Research Council Canada (MR/R024901/1)
  • ZonMw project (733051072)
  • Centre Of Excellence Neurodegenerative Diseases Agence Nationale de la Recherche (COEN-0002 and COEN-4024)
  • Agencia Estatal de Investigación (PID2019-110755RB-I00/AEI/10.13039/501100011033 and PID2022-141900OB-I00 INTO-DS)

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