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  3. Proteomics analysis of prefrontal cortex of Alzheimer's disease patients revealed dysregulated proteins in the disease and novel proteins associated with amyloid-β pathology

Proteomics analysis of prefrontal cortex of Alzheimer's disease patients revealed dysregulated proteins in the disease and novel proteins associated with amyloid-β pathology

  • Cell Mol Life Sci. 2023 May 7;80(6):141. doi: 10.1007/s00018-023-04791-y.
Ana Montero-Calle 1,  Raquel Coronel 2,  María Garranzo-Asensio 1,  Guillermo Solís-Fernández 1 3,  Alberto Rábano 4,  Vivian de Los Ríos 5,  María Jesús Fernández-Aceñero 6,  Marta L Mendes 7,  Javier Martínez-Useros 8 9,  Diego Megías 10,  María Teresa Moreno-Casbas 11 12,  Alberto Peláez-García 13,  Isabel Liste 2,  Rodrigo Barderas 14
Affiliations

Affiliations

  • 1 Functional Proteomics Unit, Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain.
  • 2 Unidad de Regeneración Neural, Unidad Funcional de Investigación de Enfermedades Crónicas, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain.
  • 3 Molecular Imaging and Photonics Division, Chemistry Department, Faculty of Sciences, KU Leuven, Celestijnenlaan 200F, Heverlee, 3001, Louvain, Belgium.
  • 4 Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation Alzheimer Center, E-28031, Madrid, Spain.
  • 5 Centro de Investigaciones Biológicas, CSIC, E-28040, Madrid, Spain.
  • 6 Surgical Pathology Department, Hospital Universitario Clínico San Carlos, E-28040, Madrid, Spain.
  • 7 Department of Infection and Immunity, Luxembourg Institute of Health, L-1445, Strassen, Luxembourg.
  • 8 Translational Oncology Division, OncoHealth Institute, Health Research Institute-University Hospital Fundación Jiménez Díaz-Universidad Autónoma de Madrid, E-28040, Madrid, Spain.
  • 9 Area of Physiology, Department of Basic Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, E-28922, Madrid, Spain.
  • 10 Advanced Optical Microscopy Unit, UCCTs, Instituto de Salud Carlos III (ISCIII), E-28220, Majadahonda, Madrid, Spain.
  • 11 Investén-isciii, Instituto de Salud Carlos III, E-28029, Madrid, Spain.
  • 12 CIBERFES, E-28029, Madrid, Spain.
  • 13 Molecular Pathology and Therapeutic Targets Group, La Paz University Hospital (IdiPAZ), E-28046, Madrid, Spain.
  • 14 Functional Proteomics Unit, Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, E-28220, Madrid, Spain. [email protected].
PMID: 37149819 DOI: 10.1007/s00018-023-04791-y
Abstract

Background: Alzheimer's disease (AD) is a progressive, chronic, and neurodegenerative disease, and the most common cause of dementia worldwide. Currently, the mechanisms underlying the disease are far from being elucidated. Thus, the study of proteins involved in its pathogenesis would allow getting further insights into the disease and identifying new markers for AD diagnosis.

Methods: We aimed here to analyze protein dysregulation in AD brain by quantitative proteomics to identify novel proteins associated with the disease. 10-plex TMT (tandem mass tags)-based quantitative proteomics experiments were performed using frozen tissue samples from the left prefrontal cortex of AD patients and healthy individuals and vascular dementia (VD) and frontotemporal dementia (FTD) patients as controls (CT). LC-MS/MS analyses were performed using a Q Exactive mass spectrometer.

Results: In total, 3281 proteins were identified and quantified using MaxQuant. Among them, after statistical analysis with Perseus (p value < 0.05), 16 and 155 proteins were defined as upregulated and downregulated, respectively, in AD compared to CT (Healthy, FTD and VD) with an expression ratio ≥ 1.5 (upregulated) or ≤ 0.67 (downregulated). After bioinformatics analysis, ten dysregulated proteins were selected as more prone to be associated with AD, and their dysregulation in the disease was verified by qPCR, WB, immunohistochemistry (IHC), immunofluorescence (IF), pull-down, and/or ELISA, using tissue and plasma samples of AD patients, patients with other dementias, and healthy individuals.

Conclusions: We identified and validated novel AD-associated proteins in brain tissue that should be of further interest for the study of the disease. Remarkably, PMP2 and SCRN3 were found to bind to Amyloid-β (Aβ) fibers in vitro, and PMP2 to associate with Aβ plaques by IF, whereas HECTD1 and SLC12A5 were identified as new potential blood-based biomarkers of the disease.

Keywords

10-plex TMT; Alzheimer’s disease; Amyloid-β interactors; Biomarkers; Liquid biopsy; Neurodegeneration; Quantitative proteomics.

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