Zempel H, Thies E, Mandelkow E, Mandelkow EM. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci. 2010 Sep 8;30(36):11938-50. PubMed.
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Comments
Laboratory for Alzheimer Disease
This manuscript is very interesting. Mandelkow’s group basically has studied many aspects of tau, such as the structure, aggregation mechanism, phosphorylation kinases, and inhibitory effect of tau on axonal transport. But the mechanism of missorting of tau from axons to somatodendrites in degenerative neurons has remained an unsolved problem for a long time in the field of AD research. In this paper, they studied the effect of Aβ on tau translocation and concluded that toxic Aβ leads to tau missorting by inducing microtubule destabilization, because taxol treatment blocked this Aβ-induced tau missorting. If microtubule disassembly is the cause of tau missorting, then how does tau move from axon to somatodendrite after detaching from the microtubule? Traveling from axon to dendrite is such a long distance, it may be that this needs a transporter instead of occurring by simple Brownian motion.
Interestingly, taxol prevents Aβ-induced missorting of tau and reduction of spine number without altering kinase activity. But MARK kinase phosphorylates the microtubule-binding region of tau, and induces dissociation of tau from microtubules. This raises interesting questions. Does Aβ activation of MARK not cause tau phosphorylation, or does phosphorylated tau stay on the microtubule?
Synapse loss is the major cause of functional loss in the AD brain. If missorting of tau induces spine loss, there must be some underlying mechanisms. However, microtubule disassembly is required for tau missorting, which means that the pre-synapse may be lost through axonal degeneration when tau is missorted to the dendrites. Which occurs first, pre-synapse, or post-synapse loss?
Most of papers start from the assumption that Aβ is a “bad guy,” and that increases in Aβ-induced synapse loss and neuron loss. Indeed, it is true in Aβ-treated cells and tissues, and in APP-Tg mice. However, removing Aβ cannot halt progression of AD. Aβ may have a physiological function, and when exaggerated, this function may cause AD dementia. However, we do not know whether Aβ has a physiological function or not. Even for tau, we do not know its physiological function other than microtubule stabilization. Studying the physiological function of key proteins in AD may help us to invent new therapeutic targets for the disease.
The University of Queensland
While Aβ and tau exert separate modes of toxicity, it is fascinating to see how more and more details are revealed about how these toxic entities interact to impair neuronal functions in dementias.
The new data presented by Lennart Mucke’s team in Science and by the Mandelkows in the Journal of Neuroscience address the fascinating interplay of Aβ and tau, the first study looking into axonal transport, and the second into sorting and morphological changes.
Tau reduction has been shown by the Mucke team in 2007 to rescue, in vivo, from Aβ lethality (Roberson et al., 2007). This was followed by our study this July, identifying the kinase Fyn as a critical mediator in executing Aβ toxicity via tau (Ittner et al., 2010). Reducing Fyn in APP transgenic mice prevents Aβ toxicity, while overexpression enhances it (Chin et al., 2005; Chin et al., 2004).
In the new study, Keith Vossel, Mucke, and colleagues transfected hippocampal neuronal cultures obtained from wild-type and tau-deficient mice with plasmids expressing fluorescent markers of mitochondria or the neurotrophin receptor TrkA to investigate axonal transport.
Interestingly, upon incubating the cultures with oligomeric Aβ preparations, they found that tau reduction protected from Aβ-induced impairments in axonal transport. This extends the beneficial effects of a tau reduction reported previously (Ittner et al., 2010; Roberson et al., 2007) to axonal transport. What I find also interesting is that baseline anterograde transport seems to be slightly reduced in the heterozygous compared to the complete tau knockout, which may indicate that compensatory mechanisms kick in when tau is fully absent, but not when it is partially reduced. Aging could yet have another effect on any phenotype, as shown recently by crossing APP mutant mice onto a tau knockout background (Dawson et al., 2010)—loss of tau exacerbated pathology. Any pharmaceutical approach aimed at reducing rather than abolishing tau levels may have similar side effects.
We previously found that both Aβ and tau cause impaired mitochondrial functions, both separately and synergistically (David et al., 2005; Rhein et al., 2009). While we looked at isolated cells or even isolated mitochondria, the advantage of the approach taken by Vossel et al. is that by imaging a tracking marker, the function of the neuron is maintained, which is different from when analyzing isolated cells or organelles as we have done. In a follow-up, it would be interesting to determine whether fibrillar preparations of Aβ cause the same effects as oligomers. For example, by looking at mitochondrial functions, such as complex activities, we previously did not detect dramatic differences between the two Aβ preparations (this was different from monomeric Aβ though, which had no effect on mitochondrial functions) (Eckert et al., 2008).
Vossel and colleagues speculate that in addition to a tau reduction, components of the axonal transport machinery may be ideal targets. I fully agree with this notion, as we had previously found that JIP1, a component of the anterograde kinesin transport machinery, is trapped by phosphorylated tau in the cell, preventing the kinesin motors from transporting distinct cargoes to the axonal terminals (Ittner et al., 2008; Ittner et al., 2009). Interestingly, tau needs to be phosphorylated to cause this impairment, which is, incidentally, rescued by a small compound activating the tau phosphatase PP2A (van Eersel et al., 2010). This demonstrates that targeting phosphorylation of tau is a suitable strategy in treating tauopathies (Iqbal and Grundke-Iqbal, 2008).
This leads me to the second paper, by Zempel and colleagues, who also used primary neuronal cultures to address the effects of Aβ oligomers on tau localization and phosphorylation. They found, upon incubating wild-type neurons with Aβ, that tau was sorted into the dendrite. We previously identified a crucial role for tau in the dendrite in executing Aβ toxicity via the NMDAR/PSD-95 complex (Ittner et al., 2010). The Mandelkow team also found that tau is differentially phosphorylated in axon and dendrite, a finding also made by us in transgenic mice overexpressing wild-type forms of human tau (Gotz and Nitsch, 2001). The work by Zempel and colleagues suggests lowering cytosolic calcium levels as an alternative strategy in treating AD.
References:
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Chin J, Palop JJ, Yu GQ, Kojima N, Masliah E, Mucke L. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J Neurosci. 2004 May 12;24(19):4692-7. PubMed.
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