Oxidative damage and antioxidant response in frontal cortex of demented and non-demented individuals with Alzheimer's neuropathology.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration in the cerebral cortex, histopathologically hallmarked by amyloid β (Aβ) extracellular plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated Tau protein. Correlation between these pathological features and dementia has been challenged by the emergence of "Non-Demented with Alzheimer's Neuropathology" (NDAN) individuals, cognitively intact despite displaying pathological features of AD. The existence of these subjects suggests that some unknown mechanisms are triggered to resist Aβ-mediated detrimental events. Aβ 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 Aβ, oxidative stress and cognitive impairment, we performed a comparative study on AD, NDAN and aged-matched human post-mortem frontal cortices of either sex. We quantitatively analyzed immunofluorescence distribution of oxidative damage markers, and of SOD2, PGC1α, PPARα, CAT as key factors in antioxidant response, as well as the expression of miRNA-485, as a PGC1α upstream regulator. Our results confirm dramatic redox imbalance, associated with impaired antioxidant defenses in AD brain. By contrast, NDAN individuals display low oxidative damage, associated with high levels of scavenging systems, possibly resulting from lack of PGC1α 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 efficient PGC1α-dependent "safety mechanism" may prevent Aβ-mediated oxidative stress, supporting neuroprotective therapies aimed at ameliorating defects in antioxidant response pathways in AD patients.SIGNIFICANCE STATEMENTThe present study importantly contributes to clarifying the molecular events underlying age-related AD pathology, emphasizing the role of antioxidant defenses against Aβ toxicity. Specifically, we addressed the mechanisms whereby a particular group of individuals, referred to as Non-Demented with AD Neuropathology (NDAN), resists dementia, despite displaying amyloid and Tau pathology consistent with fully symptomatic AD. This study reveals the ability of these individuals to activate an efficient antioxidant response to cope with oxidative stress possibly representing one of the mechanisms by which they remain cognitively intact. Our work, besides advancing the knowledge on the role of oxidative stress in AD, may lay the foundation for novel therapeutic approaches to the disease, possibly based on the activation of PGC1α-mediated antioxidant pathway.