No abstract

Oxidative stress refers to an imbalance between oxidative and antioxidative systems due to environmental factors. Although oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD), its precise role is not yet understood. We aimed to investigate the pathogenic mechanisms of the oxidative stress by using in vitro cultured neurons and in vivo AD models of PS1V97L-transgenic (Tg) mice. Our results showed that when oxidative stress became increasingly evident, the endogenous protective pathway of nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) decreased in 10-month-old PS1V97L-Tg mice. Activating the Nrf2/ ARE pathway suppressed oxidative stress, decreased amyloid-β (Aβ), and improved the cognitive function of the PS1V97L-Tg mice. In contrast, blocking the Nrf2/ARE pathway augmented oxidative injury and decreased the cell viability of PS1V97L-Tg neurons. Our results highlight the role of the Nrf2/ARE pathway in regulating oxidative stress of the PS1V97L-Tg mice and may indicate a potential therapeutic avenue for AD treatment.

Accumulating evidence has demonstrated that mitochondrial dysfunction is a prominent early event in the progression of Alzheimer's disease (AD). Whether protecting mitochondrial function can reduce amyloid-β oligomer (AβO)-induced neurotoxicity in PS1V97L transgenic mice remains unknown. In this study, we examined the possible protective effects of honokiol (HKL) on mitochondrial dysfunction induced by AβOs in neurons, and cognitive function in AD PS1V97Ltransgenic mice. We determined that HKL increased mitochondrial sirtuin 3 (SIRT3) expression levels and activity, which in turn markedly improved ATP production and weakened mitochondrial reactive oxygen species production. We demonstrated that the enhanced energy metabolism and attenuated oxidative stress of HKL restores AβO-mediated mitochondrial dysfunction in vitro and in vivo. Consequently, memory deficits in the PS1V97L transgenic mice were rescued by HKL in the early stages. These results suggest that HKL has therapeutic potential for delaying the onset of AD symptoms by alleviating mitochondrial impairment and increasing hyperactivation of SIRT3 in the pathogenesis of preclinical AD.

Background: Impairments in cognitive and emotional processing are a characteristic of major depressive disorder (MDD), and the dorsolateral prefrontal cortex (DLPFC) and amygdala are involved in these processes. However, the structural covariance between these two areas in patients with MDD has not been examined. Whether anatomical patterns are further damaged or compensated in untreated multiple-episode MDD compared to those in first-episode MDD is unclear.Methods: Structural magnetic resonance imaging was performed in 35 treatment-naïve, currently depressed patients with MDD and 35 age-, sex-, and education-matched controls. The cortical thickness and subcortical volume were calculated using FreeSurfer software. Patients were divided into two subgroups based on the previous number of episodes.Results: Regional abnormalities in patients with MDD were primarily observed in the frontal-limbic circuits. The negative structural association between the left DLPFC and left amygdala and the positive structural association between the bilateral DLPFC observed in controls were absent in patients with MDD. The medial orbitofrontal cortex and posterior cingulate cortex were thicker in patients with multiple-episode MDD than in patients with first-episode MDD and were positively correlated with disorder duration. No structural alterations were correlated with symptom severity.Conclusions: These findings may provide structural evidence for deficits in functional networks in MDD and supports an underlying structural mechanism of dysfunction involving top-down or bottom-up processes. Morphological abnormalities in the medial orbitofrontal cortex and posterior cingulate cortex may be critical for the pathophysiological progression of multiple-episode MDD.