March separate, strike together--role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer's disease.
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.
Neurobiology Laboratory, Psychiatric University Clinics Basel, University of Basel, Switzerland.
Anne
A
Eckert
Centre for Ageing Dementia Research (CADR), Queensland Brain Institute (QBI), The University of Queensland, Australia.
Rebecca
R
Nisbet
Neurobiology Laboratory, Psychiatric University Clinics Basel, University of Basel, Switzerland.
Amandine
A
Grimm
Centre for Ageing Dementia Research (CADR), Queensland Brain Institute (QBI), The University of Queensland, Australia. Electronic address: j.goetz@uq.edu.au.
Jürgen
J
Götz
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D021381:Protein Transport; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins
Alzheimer's disease; Axonal transport; DRP1; Mitochondrion; Tauopathy