Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease
Por:
Martá-Ariza, M, Leitner, DF, Kanshin, E, Suazo, J, Pedrosa, AG, Thierry, M, Lee, EB, Devinsky, O, Drummond, E, Fortea, J, Lleó, A, Ueberheide, B, Wisniewski, T
Publicada:
18 ene 2025
Resumen:
Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-beta (A beta) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the A beta plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 +/- 4.99 y/o), EOAD (63 +/- 4.07 y/o), LOAD (82.1 +/- 6.37 y/o), and controls (66.4 +/- 13.04). We identified differentially abundant proteins when comparing A beta plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R-2 = .77), DS and LOAD (R-2 = .73), and EOAD and LOAD (R-2 = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 x 10(-5)) for DS, immune system regulation (p = 4.33 x 10(-5)) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R-2 = .59) and LOAD (R-2 = .33) compared to the correlation between EOAD and LOAD (R-2 = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein-DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.
Filiaciones:
Martá-Ariza, M:
NYU, Dept Neurol, Grossman Sch Med, New York, NY 10016 USA
NYU, Ctr Cognit Neurol, Grossman Sch Med, New York, NY 10012 USA
Univ Autonoma Barcelona, Inst Neurociencies, Barcelona, Spain
Leitner, DF:
NYU, Dept Neurol, Grossman Sch Med, New York, NY 10016 USA
NYU, Ctr Cognit Neurol, Grossman Sch Med, New York, NY 10012 USA
NYU Langone Hlth, Comprehens Epilepsy Ctr, Dept Neurol, New York, NY USA
Grossman Sch Med, New York, NY USA
Kanshin, E:
NYU, Grossman Sch Med, Div Adv Res Technol, Prote Lab, New York, NY USA
NYU, Grossman Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USA
Suazo, J:
NYU, Dept Neurol, Grossman Sch Med, New York, NY 10016 USA
NYU, Ctr Cognit Neurol, Grossman Sch Med, New York, NY 10012 USA
Pedrosa, AG:
NYU, Ctr Neural Sci, New York, NY USA
Thierry, M:
NYU, Dept Neurol, Grossman Sch Med, New York, NY 10016 USA
NYU, Ctr Cognit Neurol, Grossman Sch Med, New York, NY 10012 USA
Lee, EB:
Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA
Devinsky, O:
NYU, Dept Neurol, Grossman Sch Med, New York, NY 10016 USA
NYU Langone Hlth, Comprehens Epilepsy Ctr, Dept Neurol, New York, NY USA
Grossman Sch Med, New York, NY USA
Drummond, E:
NYU, Ctr Cognit Neurol, Grossman Sch Med, New York, NY 10012 USA
Univ Sydney, Brain & Mind Ctr, Camperdown, NSW, Australia
Univ Sydney, Sch Med Sci, Camperdown, NSW, Australia
Fortea, J:
Univ Autonoma Barcelona, Hosp St Creu & St Pau, Inst Recerca IIB St Pau, Dept Neurol,Memory Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Fundacio Catalana Sindrome Down, Barcelona Down Med Ctr, Barcelona, Spain
Lleó, A:
Univ Autonoma Barcelona, Hosp St Creu & St Pau, Inst Recerca IIB St Pau, Dept Neurol,Memory Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Ueberheide, B:
NYU, Dept Neurol, Grossman Sch Med, New York, NY 10016 USA
NYU, Grossman Sch Med, Div Adv Res Technol, Prote Lab, New York, NY USA
NYU, Grossman Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USA
Wisniewski, T:
NYU, Dept Neurol, Grossman Sch Med, New York, NY 10016 USA
NYU, Ctr Cognit Neurol, Grossman Sch Med, New York, NY 10012 USA
NYU, Grossman Sch Med, Dept Pathol, New York, NY 10016 USA
NYU, Dept Psychiat, Grossman Sch Med, New York, NY 10016 USA
Green Submitted, hybrid
|