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

作者：Alexa Pichet Binette, Chris Gaiteri, Malin Wennström, Atul Kumar, Inès Hristovska, Nicola Spotorno, Gemma Salvadó, Olof Strandberg, Hansruedi Mathys, Li‐Huei Tsai, Sebastian Palmqvist, Niklas Mattsson, Shorena Janelidze, Erik Stomrud, Jacob W. Vogel, Oskar Hansson · 发表于：Nature Neuroscience · 年份：2024 · DOI：10.1038/s41593-024-01737-w · 被引用次数：119 · 研究领域：Alzheimer's disease research and treatments、Dementia and Cognitive Impairment Research、Neurological Disease Mechanisms and Treatments

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.