Proteomic changes in Alzheimer’s disease associated with progressive Aβ plaque and tau tangle pathologies
Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer's disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques and tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology in living humans. We found 127 differentially abundant proteins (DAPs) across the AD spectrum. The strongest Aβ-related proteins were mainly expressed in glial cells and included SMOC1 and ITGAM. A dozen proteins linked to ATP metabolism and preferentially expressed in neurons were independently associated with tau tangle load and tau accumulation. Only 20% of the DAPs were also altered in other neurodegenerative diseases, underscoring AD's distinct proteome. Two co-expression modules related, respectively, to protein metabolism and microglial immune response encompassed most DAPs, with opposing, staggered trajectories along the AD continuum. We unveil protein signatures associated with Aβ and tau proteinopathy in vivo, offering insights into complex neural responses and potential biomarkers and therapeutics targeting different disease stages.
Authors
- Alexa Pichet Binette (ORCID: https://orcid.org/0000-0001-5218-3337)
- Sebastian Palmqvist (ORCID: https://orcid.org/0000-0002-9267-1930)
- Erik Stomrud (ORCID: https://orcid.org/0000-0002-0841-5580)
- Atul Kumar (ORCID: https://orcid.org/0009-0000-0804-548X)
- Olof T. Strandberg
- Li‐Huei Tsai (ORCID: https://orcid.org/0000-0003-1262-0592)
- Niklas Mattsson (ORCID: https://orcid.org/0000-0002-8885-7724)
- Nicola Spotorno (ORCID: https://orcid.org/0000-0001-5404-8788)
- Inès Hristovska (ORCID: https://orcid.org/0000-0003-4779-4103)
- Oskar Hansson (ORCID: https://orcid.org/0000-0001-8467-7286)
- Gemma Salvadó (ORCID: https://orcid.org/0000-0002-5210-9230)
- Chris Gaiteri (ORCID: https://orcid.org/0000-0001-7838-8664)
- Malin Wennström (ORCID: https://orcid.org/0000-0002-9957-1801)
- Jacob W. Vogel (ORCID: https://orcid.org/0000-0001-6394-9940)
- Hansruedi Mathys (ORCID: https://orcid.org/0000-0003-0186-2115)
- Shorena Janelidze
Institutions
- University of Pittsburgh (US)
- Lund University (SE)
- SUNY Upstate Medical University (US)
- Science for Life Laboratory (SE)
- Skåne University Hospital (SE)
- Rush University (US)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2024-08-26
- DOI
- https://doi.org/10.1038/s41593-024-01737-w
- Citations
- 93
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 30.37
Funders
- BrightFocus Foundation
- Vetenskapsrådet
- Fonds de Recherche du Québec - Santé