The Distinctive Role of Tau and Amyloid beta in Mitochondrial Dysfunction through Alteration in Mfn2 and Drp1 mRNA Levels: A Comparative Study in Drosophila melanogaster.

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases. Aggregation of Aβ42 and hyperphosphorylated tau are two major hallmarks of AD. Whether different forms of tau (soluble or hyperphosphorylated) or Aβ are the main culprit in the events observed in AD is still under investigation. Here, we examined the effect of wild-type, prone to hyperphosphorylation and hyperphosphorylated tau, and also Aβ42 peptide on the brain antioxidant defense system and two mitochondrial genes, Marf (homologous to human MFN2) and Drp1 involved in mitochondrial dynamics in transgenic Drosophila melanogaster. AD is an age associated disease. Therefore, the activity of 3 antioxidant agents, CAT, SOD, and GSH levels and the mRNA levels of Marf and Drp1 was assessed in different time points of flies' life cycle. Reduction in cognitive function and antioxidant activity was observed in all lines and time points. The most and the least effect on the eye phenotype was exerted by hyperphosphorylated tau and Aβ42, respectively. In addition, the most remarkable alteration in Marf and Drp1 mRNA level was observed in transgenic flies expressing hyperphosphorylated tau when pan neuronal expression of transgenes was applied. However, when the disease causing gene expression was confined to the mushroom body, Marf and Drp1 mRNA level alteration was more prominent in tauWT and tauE14 transgenic flies, respectively. This may suggest a role for propagation of tauWT compared to hyperphosphorylated tau or Aβ42. In conclusion, in spite of antioxidant deficiency caused by different types of tau and Aβ42, it seems that tau exerts more toxic effect on the eye phenotype and mitochondrial genes regulation (Marf and Drp1). Moreover, different mechanisms seem to be involved in mitochondrial gene dysregulation when various forms of tau are expressed.