Abstract

Caspase-3 cleaved tau (TauC3) is a pathological tau modification that contributes to the pathogenesis of Alzheimer´s disease (AD). Our previous studies indicate that expression of TauC3 affects mitochondrial health inducing fragmentation, ATP loss, ROS increase, depolarization, and transport deficiencies. Mitochondrial function and the redox balance regulated by the Nrf-2 antioxidant pathway play a relevant role in synaptic communication and cognitive capacity. Here, we studied the neuroprotective effects of Nrf2 activation by sulforaphane (SFN) on mitochondrial impairment and the cognitive loss induced by TauC3 in tau knock-out (-/-) mice. Tau (-/-) mice were intrahippocampally injected with Adeno-associated (AAV) viruses containing AAV-Syn-GFP-T4 (full-length tau), AAV-Syn-GFP-T4C3 (caspase-3-cleaved tau), and AAV-Syn-GFP-P301L (tau mutation at P301L). Animals were treated with SFN and were evaluated for cognitive performance (NOR, NOL, Barnes maze tests), and mitochondrial hippocampal extracts were used to evaluate mitochondrial function. TauC3 expression affected cognitive and behavioral performance, as indicated by applying NOR, NOL, and Barnes maze tests. These adverse effects were complemented by mitochondrial dysfunction (ATP loss, depolarization, and ROS increase) induced by TauC3 in hippocampal tissue. Importantly, TauC3 mice treated with SFN (50 mg/Kg/day, two weeks) showed a significant improvement in the impaired cognitive capacity observed in TauC3 mice. These positive effects were accompanied by the improvement of mitochondrial health observed in TauC3 mice. Also, SFN treatment induced a significant increase in the expression of Nrf2-related enzymes such as TRX-1, HO-1, NQO-1, and catalase, indicating an interesting protective role of Nrf-2 pathway against neurotoxicity induced by pathological forms of tau.