Basic Science and Pathogenesis

Alzheimer's disease (AD), symptomized by cognitive decline and memory loss, is a progressive neurodegenerative disease associated with increased oxidative stress and synaptic dysfunction. Elevated levels of reactive oxygen species (ROS) negatively impact cellular components, including mitochondria. Damaged mitochondria, in turn, contribute to a further increase in ROS levels, triggering apoptotic pathway, and ultimately leading to cell death. Peroxiredoxin-V (PrxV), one of the oxidoreductive enzymes, is predominantly expressed in neurons and plays a potential role in regulating hydrogen peroxide (H₂O₂) levels, thus mitigating oxidative stress. Studies have demonstrated that PrxV prevents Aβ-induced mitochondrial fragmentation and cell death by reducing oxidative stress. Here, we aimed to examine potential dysregulation of PrxV levels in the AD brain using APP/PS1 transgenic mice at different ages.

To assess oxidative stress, we measured H₂O₂ levels in cortical and hippocampal brain tissue lysates using a hydrogen-peroxide assay kit. We evaluated oxidative stress in primary neuronal culture using CellROX dye. We also analyzed PrxV levels in synaptosomes isolated from wild-type and APP/PS1 mice using immunoblotting. Additionally, immunocytochemistry (ICC) was performed to examine PrxV levels using a primary antibody against PrxV, while mitochondrial levels were assessed using Mitotracker dye in primary cortical neurons.

In this study, APP/PS1 mice exhibited significantly increased levels of H₂O₂ in both hippocampal and cortical tissues compared to age-matched wild-type mice. Additionally, PrxV levels were significantly decreased in the synaptosomes of APP/PS1 mice compared to the wild-type group at one, three, and nine months of age. These immunoblot data were further supported by ICC, as we observed increased CellROX intensity and decreased PrxV intensity in APP/PS1 primary cortical neurons. Mitochondrial intensity was also reduced in APP/PS1 primary neurons compared to wild-type neurons.

We conclude that perturbation of PrxV levels and mitochondrial dysregulation may contribute to the increased oxidative stress as observed in APP/PS1 brain. Restoring the PrxV levels may mitigate oxidative stress and thus prevent mitochondrial dysregulation and neurodegeneration in AD.