Mass spectrometry-based proteomic profiling of human tauopathy brains suggests mitochondria-associated alterations

Tauopathies are neurodegenerative disorders characterized by intracellular accumulation of abnormal tau encoded by MAPT, yet their molecular mechanisms remain incompletely understood. We aimed to identify proteomic signatures associated with the primary tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as the secondary tauopathy Alzheimer's disease (AD), and to characterize their interaction networks. Total homogenates from the specified cortical region of postmortem brains of AD (n = 4), CBD (n = 4), PSP (n = 4), and control (n = 4) subjects were analyzed by mass spectrometry (MS). Differentially expressed proteins were subjected to functional enrichment and protein-protein interaction (PPI) network analyses. Reproducibility was assessed using JESS-based western blotting (WB), and selected candidates were examined by immunohistochemistry (IHC) and single-nucleus RNA sequencing (snRNA-seq) to evaluate cell-type-specific transcriptomic profiles. In the four-group comparison, 859, 114, 6, and 1 proteins showed P _FDR < 0.05, < 0.01, < 0.005, and < 0.001, respectively. Six proteins (AK3, ATP5PD, COX7C, PPA1, PREP, and UQCRC1) with P _FDR < 0.005 formed a highly interconnected network enriched for mitochondrial pathways, including oxidative phosphorylation and respiratory electron transport. WB validation showed strong concordance for four proteins (AK3, PREP, PPA1, and ATP5PD). IHC confirmed neuronal expression of PPA1 and PREP and revealed prominent microglial PPA1 immunoreactivity in PSP brains. snRNA-seq provided complementary cell-type-specific transcriptomic alterations. These findings suggest mitochondria-associated molecular changes shared across primary and secondary tauopathies; however, given the exploratory nature of this study, these observations should be interpreted cautiously and considered hypothesis-generating, warranting further investigation.