Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer's Neuropathology

Alzheimer's disease (AD) is characterized by progressive neurodegeneration in the cerebral cortex, histopathologically hallmarked by amyloid beta (A beta) extracellular plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. Correlation between these pathologic features and dementia has been challenged by the emergence of nondemented with Alzheimer's neuropathology (NDAN) individuals, cognitively intact despite displaying pathologic features of AD. The existence of these subjects suggests that some unknown mechanisms are triggered to resist A beta-mediated detrimental events. A beta accumulation affects mitochondrial redox balance, increasing oxidative stress status, which in turn is proposed as a primary culprit in AD pathogenesis. To clarify the relationship linking A beta, oxidative stress, and cognitive impairment, we performed a comparative study on AD, NDAN, and aged-matched human postmortem frontal cortices of either sex. We quantitatively analyzed immunofluorescence distribution of oxidative damage markers, and of SOD2 (superoxide dismutase 2), PGC1 alpha [peroxisome proliferator-activated receptor (PPAR) gamma-coactivator 1 alpha], PPAR alpha, and catalase as key factors in antioxidant response, as well as the expression of miRNA-485, as a PGC1 alpha upstream regulator. Our results confirm dramatic redox imbalance, associated with impaired antioxidant defenses in AD brain. By contrast, NDAN individuals display low oxidative damage, which is associated with high levels of scavenging systems, possibly resulting from a lack of PGC1 alpha miRNA-485-related inhibition. Comparative analyses in neurons and astrocytes further highlighted cell-specific mechanisms to counteract redox imbalance. Overall, our data emphasize the importance of transcriptional and post-transcriptional regulation of antioxidant response in AD. This suggests that an efficient PGC1 alpha-dependent safety mechanism may prevent A beta-mediated oxidative stress, supporting neuroprotective therapies aimed at ameliorating defects in antioxidant response pathways in AD patients.

Automated summary

The correlation between the pathological features of AD and dementia has been challenged by the presence of individuals with AD neuropathology but intact cognitive function. It suggests that unknown mechanisms may be triggered to resist the detrimental effects of Aβ accumulation. The study found that AD brains exhibit a dramatic redox imbalance, while NDAN individuals show low oxidative damage, possibly due to a lack of PGC1 alpha miRNA-485-related inhibition.