Similarly, in clones homozygous for milton92, a null mutation ( Glater et al., 2006), mitochondria are increased in neuronal soma but are unchanged in length ( Figure S1A). Further, reduction of miro function does not alter mitochondrial morphology in the presence of transgenic tau but is instead associated GABA receptor inhibition with increased numbers of both normal and elongated mitochondria in the neuronal cell bodies, as well as enhancement of tau neurotoxicity ( Figures S1D and S1E). Thus, elongation of mitochondria in tau transgenic animals does not appear to be a secondary effect of axonal transport defects. We next determined if tau expression can alter mitochondrial

morphology in vertebrate neurons. We used a murine model of tauopathy, rTg4510, in which human tau carrying the FTDP-17 linked P301L mutation is expressed using the CaMKIIα promoter (Ramsden et al., 2005; Santacruz et al.,

2005). To visualize mitochondria selleck screening library in histologic sections from these transgenic mice, we performed immunofluorescent staining for ATP synthase. We observe round to modestly tubular mitochondria in hippocampal pyramidal neurons of control mice (Figure 1B, control, arrowheads). In contrast, mitochondria specifically in hippocampal pyramidal neurons, a vulnerable cell population in these tau transgenic mice, have elongated morphology (Figure 1B, tau, arrowheads). Quantitative analysis reveals a significant increase in mean mitochondrial length in hippocampal neurons from tau transgenic mice (Figure 1B, ADP ribosylation factor graph). We observe similar mitochondrial elongation in a second murine model of tauopathy, K3, in which the FTDP-17-associated mutant form of tau carrying the K369I mutation is expressed under the control of the mThy1.2 promoter

(Ittner et al., 2008). Mitochondrial elongation is prominent in frontal cortical neurons, which express high levels of tau in these animals (Figure S1F). Three-dimensional reconstruction of confocal fluorescence Z-stacks captured from Drosophila and murine neurons affords a more detailed view of the elongated morphology and interconnected organization of mitochondria induced by human tau expression ( Movies S1, S2, S3, and S4). To determine if toxicity of tau to postmitotic neurons is influenced by the mitochondrial elongation we observe in animal models, we manipulated the mitochondrial dynamics machinery genetically. We focused on DRP1 and MARF (the fly homolog of mammalian MFN) and increased and decreased expression of each protein. To increase net mitochondrial fission levels, we overexpressed DRP1 and decreased levels of MARF using transgenic RNAi. These modifications significantly reduce mitochondrial length in tau transgenic flies (Figure 2A). Importantly, normalization of mitochondrial length is accompanied by significant rescue of neurotoxicity, as monitored with TUNEL staining to identify dying neurons (Figure 2B).