. 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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  1. 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.