Proteomic signatures and mitochondrial dysfunctions in peripheral T cells reveal novel ınsights into Alzheimer's disease

Abstract

Alzheimer's disease (AD) exhibits progressive cognitive decline and recent scientific studies hint to the peripheral immune system as a contributor. In this study, we isolated peripheral immune cells including CD4 + and CD8 + T cells, CD14 + monocytes and CD19 + B cells from AD patients and age-matched controls via fluorescence-activated cell sorting. Label-free LC-MS/MS-based proteomic expression analysis within each cell type, comparing AD and control groups independently, 387 significantly altered proteins were identified in CD4 + and 121 in CD8 + T cells. Bioinformatic analysis uncovered distinct, cell-type-specific signatures: CD4 + cells showed dysregulation in ribosomal and RNA-binding proteins linked to neurodegeneration and oxidative stress while CD8 + cells showed elevated glycolytic enzyme expression and hyperpolarized mitochondrial membrane potential. Furthermore, mitochondrial functional assays, JC-1 and MitoSOX Red, further supported cell-type-dependent differences in mitochondrial activity. These findings may suggest that peripheral T cells have unique proteomic and functional alterations in AD, implicating mitochondrial dysfunction as a potential contributor to disease pathology.