Tau and axonal transport

Abstract

The established physiological functions of tau include the stabilization of microtubules and the promotion of neurite outgrowth (Mandelkow & Mandelkow, 1998; Garcia & Cleveland, 2001). More recently it was recognized that tau can regulate the transport of cell components by molecular motors along microtubules (Ebneth et al., 1998). Tau influences the rates of attachment and detachment of motors from microtubules (Trinczek et al., 1999). The result is that movements towards the cell center become predominant. This leads to the gradual retraction of cell components such as the ER, mitochondria or peroxisomes. Starting from these observations one can ask what the effect of tau would be on highly asymmetric cells such as neurons. Tau is the predominant MAP in axons (Binder et al., 1985); if the plus-end directed transport were retarded by tau this would hinder the supply of material into the axons and dendrites, with subsequent damage to synapses. This may be significant in the context of Alzheimer's disease where the affected neurons appear to contain higher levels of tau protein (Khatoon et al., 1992). We therefore analyzed the distribution of cytoskeletal components, organelles, and Golgi-derived vesicles and their dependence on tau. A consistent interpretation of the combined data is that tau inhibits transport along microtubules, preferentially in the anterograde direction. The consequence is that organelles tend to be excluded from cell processes, and vesicles are strongly reduced. A further consequence is that axonal and dendritic compartments become more vulnerable. The movement of organelles, vesicles and neurofilaments is consistent with the view that these components are transported anterogradely by a kinesin-dependent transport (Hollenbeck & Saxton, 2005). Remarkably, the inhibition of anterograde transport does not apply to microtubules or microtubule-associated proteins such as tau, presumably because their transport takes place by a different type of mechanism, for example by dynein-dependent transport along actin filaments (Baas & Buster, 2004). The transport inhibition can have profound consequences for the survival of cell processes. Thus, tau-transfected cells become highly sensitive to oxidative stress, consistent with the lack of peroxisomes. Similarly, the exclusion of mitochondria from the cell processes means that ATP is locally depleted. This is tantamount to a loss of mitochondrial function in the neurites. One can speculate what these observation mean for neurodegenerative disorders such as Alzheimer's disease and other tauopathies which are characterized by locally elevated and aggregated tau protein. One of the earlierst detectable signs is the faulty distribution of tau in the somatodendritic compartment, the loss of synapses and retrograde degeneration ("dying back") of neurons which is accompanied by a decay of intracellular transport (Terry et al., 1991; Coleman & Yao, 2003). This may be accompanied by an elevation of non-fibrillar forms of Aβ (Walsh & Selkoe, 2004). APP is considered to have neurotrophic functions and is transported on kinesin-driven vesicles. It has been proposed that the C-terminal domain of APP interacts directly with a kinesin light chain (Kamal & Goldstein, 2002), although this notion has recently been challenged (Lazarov et al., 2005). Independently of these issues, the local elevation of tau presents obstacles to traffic, such that APPvesicles tend to disappear from the axons and dendrites and APP becomes trapped in the cell body. This could potentially lead to an elevation of Aβ generated in the trans-Golgi network (Greenfield et al., 1999), although this has not observed experimentally for reasons discussed elsewhere (Goldsbury et al., 2006). By contrast, the transport infrastructure is less dependent on tau than vesicle or organelle traffic since microtubule tracks survive long after mitochondria, APP-vesicles and others have disappeared from the cell body, but eventually microtubules disappear as well when the cell processes degenerate. We can therefore distinguish three types of tau toxicity related to intraneuronal transport: (i) Tau causes a slowdown of anterograde traffic which leads to starvation of neurites and missorting of tau into the somatodendritic compartment. (ii) The cell responds by activating kinases, which results in the detachment of tau from microtubules and their destabilization, (iii) unbound tau aggregates into neurofibrillary tangles which obstruct the cytoplasm. © 2007 Springer Science+Business Media, LLC. All rights reserved.