ABSTRACT: Background: The molecular mechanisms of tauopathies, characterized by intracellular accumulation of abnormal tau encoded by MAPT, remain poorly understood. Objectives: To identify proteins associated with the primary tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as the secondary tauopathy Alzheimer’s disease (AD), using mass spectrometry. Methods: Total homogenates were prepared from human postmortem brains of AD (n = 4), CBD (n = 4), PSP (n = 4), and their respective controls (n = 4), and analyzed by mass spectrometry. Protein levels were compared across the four groups, and proteins showing statistically significant differences were subsequently examined using functional enrichment and protein–protein interaction (PPI) analyses. For a subset of the proteins that showed significant differences, immunohistochemistry was performed to determine their distribution in the brain. Furthermore, single-nucleus RNA sequencing data were analyzed to evaluate the corresponding gene expression across the four groups in a cell-type–specific manner at the RNA level. Results: In the four-group comparison, 859, 114, 6, and 1 proteins showed P values < 0.05, < 0.01, < 0.005, and < 0.001, respectively. We subsequently focused on the six proteins with P values < 0.005 (AK3, ATP5PD, COX7C, PPA1, PREP, and UQCRC1) and performed functional enrichment and PPI analyses. These analyses revealed that the identified tauopathy-related proteins were shown to be mainly involved in mitochondrial function. Discussion: Age-related mitochondrial dysfunction could influence the onset and progression of tauopathies.
