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Proteomic changes in Alzheimer’s disease associated with progressive Aβ plaque and tau tangle pathologies

Pichet Binette, Alexa LU ; Gaiteri, Chris LU ; Wennström, Malin LU ; Kumar, Atul LU orcid ; Hristovska, Ines LU ; Spotorno, Nicola LU ; Salvadó, Gemma LU ; Strandberg, Olof LU ; Mathys, Hansruedi and Tsai, Li Huei , et al. (2024) In Nature Neuroscience 27(10). p.1880-1891
Abstract

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,... (More)

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.

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Please use this url to cite or link to this publication:
@article{3a7e8aa5-5fd3-459a-806a-566c2f2699fe,
  abstract     = {{<p>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.</p>}},
  author       = {{Pichet Binette, Alexa and Gaiteri, Chris and Wennström, Malin and Kumar, Atul and Hristovska, Ines and Spotorno, Nicola and Salvadó, Gemma and Strandberg, Olof and Mathys, Hansruedi and Tsai, Li Huei and Palmqvist, Sebastian and Mattsson-Carlgren, Niklas and Janelidze, Shorena and Stomrud, Erik and Vogel, Jacob W. and Hansson, Oskar}},
  issn         = {{1097-6256}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{1880--1891}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Neuroscience}},
  title        = {{Proteomic changes in Alzheimer’s disease associated with progressive Aβ plaque and tau tangle pathologies}},
  url          = {{http://dx.doi.org/10.1038/s41593-024-01737-w}},
  doi          = {{10.1038/s41593-024-01737-w}},
  volume       = {{27}},
  year         = {{2024}},
}