Among the explanations offered for tau’s detrimental effects on neurons in Alzheimer disease is that elevations in tau levels, and/or changes in its cellular distribution, disrupt microtubule function and axonal transport. This hypothesis rests on evidence garnered from cultured neurons and from studies with purified microtubules and motor proteins in vitro. That work suggests that simply raising tau levels is enough to inhibit axonal transport and cause degeneration of synapses (see ARF related news story and ARF news story).
However, the result does not readily translate in vivo, according to new data from Aidong Yuan, Ralph Nixon, and colleagues at the Nathan Kline Institute, Orangeburg, New York, and New York University. Measuring axonal transport in the optic nerve of mice that either overexpress the long form of human tau, or have no tau at all, these investigators detect no alteration whatsoever in the overall speed of axonal transport or in the movement of select cargo proteins.
”These findings show that axonal transport is not necessarily dependent on the presence of tau and is not significantly inhibited by moderately elevated levels of tau,” the investigators write in a paper published in the February 13 issue of the Journal of Neuroscience.
To assess slow axonal transport, the researchers injected radiolabeled 35S-methionine into the vitreous of the eye, after which they dissected the optic nerve and looked at how far the radioactivity had traveled up the nerve tract. In tau knockout mice, global transport was unchanged, as measured by bulk radioactivity levels along the optic nerve tract 1 to 2 weeks after injection. Neither was slow transport affected, as measured by the progress of labeled neurofilament proteins and other cargos over the same time frame. Fast transport was measured by tracking 35S-labeling 5 hours after injection, and likewise revealed no alteration in the absence of tau.
Mice overexpressing tau yielded similar results. The radioactivity measurements were supported by additional immunohistochemistry and electron microscopy imaging, which revealed a normal steady state distribution of proteins and organelles in all the mice.
The reasons for the discrepancies between the in vivo and in vitro results of tau overexpression are unclear. The animals used in this study had twofold elevated tau in their retina and fourfold elevated protein in their optic nerve, but no evidence of changes in tau phosphorylation or solubility. The results, the authors write, “do not exclude the possibility that tau may interfere with axonal transport when overexpressed at extremely high levels or when its isoform composition or phosphorylation state is altered significantly.”
In support of the in vivo results, previous in vitro studies of transport in squid axon preparations found no effect of monomeric tau, unless the protein was added at very high concentrations, where it began to inhibit transport non-specifically (Morfini et al., 2007).
Both elevation and depression of tau levels have been reported in AD brain (Ksiezak-Reding et al., 1988; Khatoon et al., 1992). Changes in tau’s subcellular distribution from its normal place in axons to the somatodendritic compartment in the form of neurofibrillary tangles could result in a lack of properly functioning protein in AD brain. However, the current study raises questions about whether these alterations have pathological consequences on axonal transport, and pose anew the question of exactly how tau relates to neurodegeneration. Evidence from AD and also from the tauopathies, a separate family of dementias where mutations in tau itself cause neurodegeneration, suggests that hyperphosphorylation, truncation, or aggregation of tau are important in neurodegeneration. More in vivo studies will surely help settle the question of whether those changes influence axonal transport.—Pat McCaffrey
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- Morfini G, Pigino G, Mizuno N, Kikkawa M, Brady ST. Tau binding to microtubules does not directly affect microtubule-based vesicle motility. J Neurosci Res. 2007 Sep;85(12):2620-30. PubMed.
- Ksiezak-Reding H, Binder LI, Yen SH. Immunochemical and biochemical characterization of tau proteins in normal and Alzheimer's disease brains with Alz 50 and Tau-1. J Biol Chem. 1988 Jun 15;263(17):7948-53. PubMed.
- Khatoon S, Grundke-Iqbal I, Iqbal K. Brain levels of microtubule-associated protein tau are elevated in Alzheimer's disease: a radioimmuno-slot-blot assay for nanograms of the protein. J Neurochem. 1992 Aug;59(2):750-3. PubMed.
- Yuan A, Kumar A, Peterhoff C, Duff K, Nixon RA. Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci. 2008 Feb 13;28(7):1682-7. PubMed.