Alterations of transcription of genes coding sirtuins and proteins involved in mitochondrial dynamics in amyloid β toxicity in experimental model of Alzheimer's disease

A growing body of evidence indicates that mitochondrial dysfunction is one of the earliest alterations responsible for progression of Alzheimer's disease (AD). Mitochondria are the main source of reactive oxygen species (ROS) but also the main target of ROS. Amyloid β (Aβ), which contributes to neuronal degeneration and synaptic loss in AD, accelerates ROS generation and possibly triggers a 'vicious cycle': ROS – mitochondrial impairment – ROS. Increasing evidence indicates that sirtuins have neuroprotective effects in regulating oxidative stress and metabolism. The mechanisms by which Aβ oligomers affect mitochondria as well as the role of sirtuins in AD-related hypometabolism remain not entirely understood. The aim our study was to analyse the impact of exogenous Aβ1-42 oligomers (AβO) and endogenously liberated Aβ peptides on transcription of genes for sirtuins and mitochondrial dynamics -related proteins in cell lines (neuronal SH-SY5Y and microglial BV2) and in brain cortex of transgenic AD (Tg-AD) mice. Our results demonstrated significant AβO-evoked changes in transcription of genes in SH-SY5Y cells, where AβO enhanced expression of Sod1 and Cat, attenuated Sirt5 and Sod2. In BV2 line, AβO increased the level of mRNA for Sod2 and Dnm1l, decreased for Sirt1, Sirt3, Gpx4 and Mfn2. AβO enhanced free radical level and impaired mitochondrial membrane potential only in SH-SY5Y cells, but reduced viability of both cell types. Activators of Sirt1 more efficiently enhanced viability of SH-SY5Y than BV2 affected by AβO. Analysis of brain cortex of Tg-AD mice confirmed significant downregulation of Sirt1 and Mfn1 and upregulation of Dnm1l. In human AD brain, changes of microRNA pattern (miRNA-9, miRNA-34a, miRNA-146a and miRNA-155) seem to be responsible for decrease in Sirt1 expression. Overall, our results demonstrated a diverse response of neuronal and microglial cells to AβO toxicity. Alterations of genes encoding Sirt1 and proteins involved in mitochondrial dynamics suggest that modulation of Sirt1 and Drp1, including miRNA strategy, may be crucial for improvement of AD therapy. This work was supported by Statute Theme No 5, by Grant NCN-2014/2015/B/NZ3/01049 and grant to the LSU Eye Center from Research to Prevent Blindness (RPB); the Louisiana Biotechnology Research Network (LBRN) and NIH grants NEI EY006311, NIA AG18031 and NIA AG038834 (WJL).