Linking ER–Mitochondria Calcium Flux to Oxidative Stress and Protein Clearance Deficits in Alzheimer’s Disease

Overview

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction, impaired protein clearance, and accumulation of pathological aggregates. Analyzed a multidimensional dataset comprising control, mild cognitive impairment (MCI), early AD, and late AD human brain samples. Investigated mitochondrial reactive oxygen species (ROS), autophagic flux, lipid peroxidation (4-HNE), mitochondrial dynamics (Mitofusin 2), lysosomal abundance, and amyloid peptide ratios (Aβ42/Aβ40). Results reveal a strong positive correlation between AD progression and both mitochondrial ROS and Aβ42/Aβ40 ratios, highlighting increased oxidative stress and amyloidogenic burden with disease severity. Conversely, autophagic flux showed a robust decline, while 4-HNE levels rose significantly in late AD, indicating impaired clearance mechanisms and elevated oxidative damage. Lysosome abundance increased in late-stage AD, potentially reflecting compensatory or dysfunctional remodeling. Mitofusin 2 expression exhibited moderate upregulation with progression, consistent with altered mitochondrial–ER tethering. Collectively, these findings provide an integrated view of mitochondrial stress, protein aggregation, and clearance pathway dysfunction across AD stages.