Oxidative Stress during the Progression ofβ-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by β-amyloid (Aβ) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of Aβ pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of Aβ peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1α expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPARα is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular Aβ accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes.

DNA Demethylation Upregulated Nrf2 Expression in Alzheimer’s Disease Cellular Model

“…Cumulative evidence has demonstrated that oxidative stress is inextricably linked with several major pathological processes in AD (Sheng et al, 2009 ; Clausen et al, 2012 ; Porcellotti et al, 2015 ). Nrf2, a pivotal regulator of endogenous defense systems against oxidative stress, is decreased in AD brain tissue (Kanninen et al, 2009 ).…”

Silver nanoparticle-induced expression of proteins related to oxidative stress and neurodegeneration in an in vitro human blood-brain barrier model

“…We also observed that the anti-oxidative proteins glutathione peroxidase (Gpx1) and glutathione peroxidase (Gpx4), known for their protective roles against oxidative stress, were downregulated. Expression of Gpx1 and Gpx4 has been shown to be reduced in a mouse model of AD and Parkinson disease (PD) (Zhang et al 2016;Porcellotti et al 2015). Studies have shown that reduced levels of Gpx1 and Gpx4 lead to neurotoxicity-mediated neurodegeneration (Zemolin et al 2012;Yoo et al 2010;Bellinger et al 2011).…”

The Alzheimer's disease–protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool

“…Peroxisome dysfunction (either resulting from a peroxisome biogenesis or a single enzyme defect) has been identified in severe demyelinating and neurodegenerative brain diseases (43). Recent evidence suggests that increased oxidative stress during LOAD progression is accompanied by loss of peroxisomes (44). Studies also point to functional and biogenetic relationships linking peroxisomes to mitochondria and suggest peroxisomal proteins as biomarkers/ therapeutic targets in pre-symptomatic Alzheimer's disease (45).…”