. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010 Dec 22;68(6):1067-81. PubMed.

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  1. The paper from Lennart Mucke’s group demonstrates that Aβ-induced synaptic dysfunction depends upon cellular alterations in tau proteins. In contrast, our paper (Hoover et al., 2010) mainly focuses on how cellular alterations in tau proteins themselves impair synaptic functions. There is a possibility, although not proven, that the cellular mechanism unraveled by our study underlies the signaling steps downstream from the cellular alterations found by Mucke’s group. These two studies fit well to each other and both support this possible hypothesis.

    References:

    . Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010 Dec 22;68(6):1067-81. PubMed.

    View all comments by Dezhi Liao
  2. This is nice work by Hoover and colleagues providing yet another piece of important evidence for the role(s) of tau in the post-synapse. While we showed before that endogenous mouse tau is associated with the post-synaptic density (PSD) (Ittner et al., 2010), this study now reveals that upon overexpression of human tau, even more tau is associated with the PSD (in particular, when the P301L mutations is present), which then impairs the normal function of synapses. I am particularly intrigued by the fact that (hyper)phosphorylation of tau specifically promotes its localization to dendritic spines.

    References:

    . Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. PubMed.

  3. In this manuscript, Hoover and colleagues report that overexpressed tau distributes to dendritic spines, where it impairs synaptic responses. The results suggest that not only does tau lead to pre-synaptic dysfunction by impairing axonal transport, but it also causes post-synaptic dysfunction that contributes to behavioral deficits in mice overexpressing mutant tau. The importance of post-synaptic function through tau was also suggested by a previous report (Ittner et al., 2010). Therefore, tau may play a role in the post-synapse, directly or indirectly, leading to neural dysfunction in neurodegenerative disease. However, because the localization of tau in dendritic spines is shown only in a tau overexpression paradigm, we need to know whether or not endogenous tau also distributes to the dendritic spine in disease cases before we consider tau a therapeutic target.

    In AD or the other tauopathies, tau is not overexpressed in neurons, and it relocates from the axon to the somatodendrite when tau is hyperphosphorylated. In this manuscript, Hoover et al. show that when overexpressed, pseudophosphorylated tau localizes in the dendrite/dendritic spine. There are two possible mechanisms. One is that phosphorylated tau diffuses to somatodendrite, because it no longer associates with microtubules. The other is that phosphorylated tau is transported to the dendrite by some unknown active mechanisms. If tau is basically found in axons under normal conditions, then is phosphorylated tau in somatodendrites derived from axonal tau? If so, phosphorylated tau travels a long distance, and there must be some physiological reason for hyperphosphorylated tau to travel this long distance to the dendrite/dendritic spine. Alternatively, tau may localize in locations other than the axon, where it plays a physiological role under normal conditions, and accumulates in dendrites by hyperphosphorylation. Therefore, we may need to pay more attention to localization of endogenous tau (not overexpressed tau), and to other possible indispensable roles of tau besides microtubule stabilization, in normal conditions.

    Finally, I have a question about this result. Hoover and colleagues indicated that P301L tau accumulated in dendritic spines in transgenic mice, primary neuronal culture of the transgenic mouse, and when overexpressed in rat primary neurons. The accumulation of P301L tau reduces AMPA receptor levels, leading to memory deficit before synapse loss and neuron loss. If the accumulation of P301L tau in the synaptic region is a cause of synaptic dysfunction, why did the 1.3-month-old mouse not show learning deficit, while the 4.5-month-old mouse did? The tau expression level is similar in both.

    Also, in this week’s Journal of Neuroscience, Mucke’s group reported that reduction of tau rescued synaptic dysfunction in an APP Tg mouse, which again makes us more pay attention to the role of tau in synaptic function. Furthermore, the results make us consider not only NMDA signals, but also “homeostatic synaptic plasticity” to better understand development of dementia in AD.

    View all comments by Akihiko Takashima