Workshop 4

Impaired axonal transport has been proposed as a pathomechanism in neurodegenerative diseases such as Alzheimer’s disease (AD). With axons in humans exceeding a meter in length, and as neurons are generally not renewed, it is not surprising that these cells are highly vulnerable to any perturbation of the transport machinery. Intracellular transport is mainly achieved by microtubule-dependent trafficking. Microtubules are assembled from proteins such as tau, and heterodimers of aand b-tubulin. A role for oxidative stress has also been suggested in AD. As the functioning of a neuron is dependent on the transport of mitochondria to the nerve terminal, and as mitochondria are the primary site of the production of reactive oxygen species, the axonal transport and oxidative stress hypothesis in AD are tightly linked. Transgenic models have been instrumental in dissecting pathomechanims (Götz and Ittner, Nat. Rev. Neurosci. 9: 532–544, 2008). We addressed the role of tau in axonal transport initially by expressing wild-type human tau in transgenic mice which caused the formation of axonal spheroids containing cytoskeletal elements and mitochondria (Probst et al., Acta Neuropathol (Berl). 99: 469–481, 2008). More recently, we expressed different mutant forms of tau including K369I tau (a mutation found in Picks disease) which caused memory impairment and parkinsonism, along with timpaired axonal transport of mitochondria, the adaptor protein Jip1 and tyrosine hydroxylase (TH)-containing vesicles (Ittner et al., Proc. Natl. Acad. Sci.U.S.A. 105: 15997–16002, 2000). Together this demonstrates a central role of tau in pathogenesis.