No abstract

This study aimed to investigate the effect of circ_0000950/miR-103 network on regulating neuron apoptosis, neurite outgrowth and inflammation in Alzheimer's disease (AD). Cellular AD model of rat pheochromocytoma cell line PC12 cells and cellular AD model of rat cerebral cortex neurons were constructed, and the effect of circ_0000950 on apoptosis, neurite outgrowth and inflammation in both cellular AD models was determined through upregulation and knockdown of circ_0000950 expression by transfection. Compensation experiments and luciferase assay were further performed to validate the sponging effect of circ_0000950 on miR-103 as well as the mechanisms of circ_0000950/miR-103 on regulating apoptosis, neurite outgrowth and inflammation in both cellular AD models. Circ_0000950 reduced miR-103 expression and increased prostaglandin-endoperoxide synthase 2 (PTGS2) expression in both two cellular AD models. And circ_0000950 overexpression promoted neuron apoptosis, suppressed neurite outgrowth and elevated IL-1β, IL-6 and TNF-α levels compared with overexpression control, whereas circ_0000950 knockdown inhibited neuron apoptosis, enhanced neurite outgrowth and lowered IL-1β, IL-6 and TNF-α levels compared with shRNA control in both two cellular AD models. Compensation experiments along with luciferase reporter assay validated that circ_0000950 promoted cell apoptosis, suppressed neurite outgrowth and elevated inflammatory cytokines levels via directly sponging miR-103. In conclusion, circ_0000950 promotes neuron apoptosis, suppresses neurite outgrowth and elevates inflammatory cytokines levels through directly sponging miR-103 in AD.

The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young (3-7-month-old) transgenic mice overexpressing mutant amyloid precursor protein (APP) abolished the phenotype of the APP AD model. This evidence is complicated by the uncertain impact of overexpressing mutant APP, rather than Aβ alone, and for potential interactions between tau and overexpressed APP. Cortical iron elevation is also implicated in AD, and tau promotes iron export by trafficking APP to the neuronal surface. Here, we utilized an alternative model of Aβ toxicity by directly injecting Aβ oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against Aβ-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human Aβ being eliminated after 5 weeks, enduring changes, including increased APP levels, tau reduction, tau phosphorylation, and iron accumulation, were observed. While the results from our study support the amyloid cascade hypothesis, they also suggest that downstream effectors of Aβ, which propagate toxicity after Aβ has been cleared, may be tractable therapeutic targets.