Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci. 2011 Jan 12;31(2):700-11. PubMed.

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  1. I am intrigued by the findings regarding changes in transmission in the dentate gyrus of APP Tg animals. The authors find an increase in miniature inhibitory post-synaptic (IPSC) current frequency, but a decrease in "spontaneous" IPSC frequency (a question regarding "spontaneous" is that this is an isolated slice lacking cell bodies of many of the normal inputs—e.g., entorhinal cortex). I note that they confirm in the dentate gyrus what we have seen in the CA1 region: a reduced mini-excitatory post-synaptic current frequency. All these changes somehow contribute to changes in network activity.

    The question regarding which changes are primarily due to Aβ and which are compensatory is important. My feeling is that this question must be answered with more acute treatments: Making inferences regarding this question based on transgenic animals is almost impossible; it would require making causal inferences over time and development (from before birth to the time when the transgenic animal is analyzed) that would explain the phenotype.

    Given our (and others') findings that acute (minutes to days) Aβ treatment produces a reduction of excitatory transmission, it would seem that this should be considered a primary cause of the eventual phenotype observed in these animals. More careful assessment of Aβ effects on inhibitory neurons (transmission as well as spiking) is warranted.

    It will be also important to determine if the primary changes produced by enhanced Aβ lead to subsequent changes that produce a vicious (positive reinforcement) cycle that exacerbates the phenotype. For instance, increased Aβ produces a reduction in excitatory transmission, leading to hypoactivity of interneurons, which leads to increased network activity, which increases Aβ production/release. Interfering with this vicious cycle may prove therapeutically beneficial.

    View all comments by Roberto Malinow

  2. 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:

    Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D. 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

  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

  4. This paper by Erik Roberson, Lennart Mucke, and colleagues sheds new light on the susceptibility of APP transgenic mice to seizures. Accumulating evidence suggests that vulnerability to epilepsy is one aspect of Alzheimer’s disease where both amyloid and tau pathologies may be required. Mucke’s group earlier reported that mice expressing hAPP with the Swedish and Indiana mutations (either the high-expressing J20 line or the low-expressing J9 line sensitized to pathogenic Aβ effects by neuronal overexpression of Fyn) show reduced seizure threshold after systemic pentylenetetrazole (PTZ) administration, and aberrant calbindin and neuropeptide Y expression in the hippocampus similar to rodents with induced seizures (Palop et al., 2007). We reported similar histochemical changes in APPswe/PS1dE9 mice with generalized spontaneous seizures (Minkeviciene et al., 2009). The Mucke team also reported that reduction of endogenous tau by crossing hAPP mice with tau-/- mice prevents premature mortality and increases the threshold to kainic acid-induced seizures in J20 mice (Roberson et al., 2007). The present paper first confirms the protective role of tau reduction on early mortality in the hAPP/J9+ Fyn line and in another hAPP mouse line (TASD41, which expresses hAPP with the Swedish and London V717I mutations), but not in SOD1 transgenic mouse models of amyotrophic lateral sclerosis. Tau reduction also prevented increased susceptibility to PTZ-induced seizures and ameliorated the severity of spontaneous seizures in hAPPJ9/Fyn mice as well as in the hAPPJ20 mice.

    What might be the specific Aβ-tau interaction that renders amyloid-producing mice susceptible to epileptic seizures? Despite a large number of data, this key question is only briefly discussed in the paper. Of note in the present paper, the anti-convulsive effect of tau knockout was not restricted to hAPP mice, but was observed in Fyn transgenics or even wild-type mice. Similarly, tau reduction markedly suppressed bicucullin-induced epileptiform bursting in hippocampal slices from both non-transgenic and hAPPJ20 mice. However, some network effects of tau knockout were specific to hAPP mice. Dentate granule cells of hAPPJ20 mice showed increased frequency of miniature inhibitory post-synaptic potentials, while mini-excitatory post-synaptic potentials were increased compared to wild-type controls. Tau reduction prevented both types of changes in hAPP mice but had no effect in wild-type mice. Similarly, NMDA receptor-mediated currents in dentate granule cells were reduced, while AMPA-currents were unchanged in hAPPJ20 mice. The NMDA effect, too, was blocked by tau reduction in hAPP mice, while no effect of tau reduction was observed in wild-type mice.

    The change in NMDA currents links the current paper in an interesting way to a recent observation by Ittner and colleagues (Ittner et al., 2010). They crossed yet another hAPP mouse line (APP23) with tau-/- mice or mice expressing a truncated form of tau that prevented its interaction (via its amino-terminal domain) with the fyn kinase. Fyn phosphorylates the NMDA receptor NR2B subunit to facilitate its interaction with post-synaptic density protein 95, further linking the NMDA receptor to synaptic excitotoxic downstream signaling. Interestingly, both knockout or truncation of tau ameliorated premature mortality of APP23 mice, and reduced their susceptibility to PTZ induced seizures.

    Further evidence for the role of the tau-fyn interaction in premature mortality and seizure susceptibility of APP transgenic mice comes from fyn transgenic mice. These animals present with seizures and premature mortality (Kojima et al., 1998), and these are exacerbated in mice co-expressing transgenic APP (Chin et al., 2004; Roberson 2011). It remains to be seen whether the tau-fyn interaction can be linked to the initial seizure susceptibility of APP transgenic mice or only to the mortality associated with the seizures. Judged from the electrophysiological findings in the present paper, tau may also be involved in the network plasticity that changes the excitation-inhibition balance.

    References:

    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.

    Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22 PubMed.

    Kojima N, Ishibashi H, Obata K, Kandel ER. Higher seizure susceptibility and enhanced tyrosine phosphorylation of N-methyl-D-aspartate receptor subunit 2B in fyn transgenic mice. Learn Mem. 1998 Nov-Dec;5(6):429-45. PubMed.

    Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fülöp L, Penke B, Zilberter Y, Harkany T, Pitkänen A, Tanila H. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci. 2009 Mar 18;29(11):3453-62. PubMed.

    Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. PubMed.

    Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.

    View all comments by Heikki Tanila

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