March separate, strike together — Role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer's disease

• TAU and Abeta separately and synergistically impair mitochondrial functions.
• Suitable animal models are the SAMP and Harlequin strains and TAU transgenic mice.
• TAU specifically impairs complex I and Abeta complex IV.
• TAU impairs mitochondrial transport.
• TAU impairs mitochondrial dynamics favouring mitochondrial elongation.

The energy demand and calcium buffering requirements of the brain are met by the high number of mitochondria in neurons and in these, especially at the synapses. Mitochondria are the major producer of reactive oxygen species (ROS); at the same time, they are damaged by ROS that are induced by abnormal protein aggregates that characterize human neurodegenerative diseases such as Alzheimer's disease (AD). Because synaptic mitochondria are long-lived, any damage exerted by these aggregates impacts severely on neuronal function. Here we review how increased TAU, a defining feature of AD and related tauopathies, impairs mitochondrial function by following the principle: ‘March separate, strike together!’ In the presence of amyloid-β, TAU's toxicity is augmented suggesting synergistic pathomechanisms. In order to restore mitochondrial functions in neurodegeneration as a means of therapeutic intervention it will be important to integrate the various aspects of dysfunction and get a handle on targeting distinct cell types and subcellular compartments. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.