Though typically considered an axonal protein in neurons, tau is found in dendrites in the brains of people with Alzheimer’s and other neurodegenerative disorders. More recent studies have reported tau in dendrites under normal physiological conditions as well, and researchers are beginning to tease out its role there in both health and disease. At the Society for Neuroscience annual meeting held November 9–14 in San Diego, scientists nailed dendrites as the source of the tau-dependent neuronal hyperexcitability in AD mice and proposed a role for the microtubule binding protein in postsynaptic signaling.

Back when he was a postdoc in Lennart Mucke’s lab at the Gladstone Institute for Neurological Disease in San Francisco, Erik Roberson found that crossing J20 APP transgenic mice with tau knockouts reduced spontaneous seizures (Sep 2007 news storyMay 2007 news story). He then found that knocking out tau not only normalized network activity in other mouse models of AD but also in mice modeling epilepsy (Roberson et al., 2011; see also May 2011 conference storyJan 2013 news story). In adult mice susceptible to seizures, suppressing tau also suppressed the convulsion (DeVos et al., 2013).

At SfN, Roberson, who is now at the University of Alabama, Birmingham, presented his lab’s latest work delving into mechanisms behind this protection. The scientists wondered how dendritic tau regulates neuronal excitability in AD mice.

To address that question, the researchers collaborated with Ben Throesch in Dax Hoffman’s lab at the National Institutes of Health, Bethesda, Maryland. This is one of the few research groups with expertise in dendritic patch-clamps (Davie et al., 2006). Analyzing the J20 mice, the scientists found that their dendrites spiked more robustly than non-transgenic littermates. This was evidenced by higher-amplitude action potentials transmitted away from the soma toward the dendrites. These back-propagating pulses are a standard measure of dendritic excitability. No such changes were detected in the rest of the cell. This “localizes the neuronal hyperexcitability we see at the network level to dendrites,” Roberson suggested. 

To probe the molecular basis for the defect, Alicia Hall in Roberson's lab examined the three primary channels that regulate excitability in dendrites. In J20 mice, the CA1 and dentate gyrus expressed lower levels of the Kv4.2 potassium channel, relative to non-transgenic littermates, whereas levels of the other two (HCN1 and HCN2) remained unchanged, Roberson reported. The potassium current Kv4.2 carries is hyperpolarizing, and less Kv4.2 is known to increase dendritic excitability. How dendritic tau might reduce expression of the potassium channel remains a mystery. 

Loss of Kv4.2 affects behavior, as well. When the researchers mated the mildly amyloidogenic J9 strain with Kv4.2 knockout mice (Guo et al., 2005), the crosses performed worse in short-term spatial memory tasks that J9 mice typically handle with ease, Roberson said. In tau-deficient APP mice, dendritic excitability looked normal. 

At SfN, Lars Ittner of the University of Sydney proposed another role for tau, that is, regulation of postsynaptic signaling through the kinase ERK. This line of work began when the scientists noticed that tau knockout mice do not turn on expression of the immediate early genes (IEG) fos, arc, and JunB in response to pentylenetetrazol (PTZ), a seizure-inducing compound. Checking upstream of IEGs, the researchers found no ERK phosphorylation, and even further upstream, only weakly active synaptic Ras in brain slices from these tau-deficient mice. The wan activity of Ras was not due to its concentration, but rather due to an excess of its inhibitor SynGAP1. This Ras-GTPase activating protein occupies synaptic complexes with postsynaptic density protein 95 (PSD-95) and NMDA receptors. “Levels of this endogenous Ras inhibitor are massively increased in dendritic spines of tau knockout mice,” Ittner reported. This hints that something changes in the PSD-95 complex to allow more SynGAP1 to bind, and that then keeps Ras, and therefore ERK, turned off when NMDA receptors are activated, he suggested.

The work would suggest that tau keeps SynGAP1 away from the PSD-95 complex. Ittner and colleagues are still trying to figure out how that happens. In the meantime, they and other researchers are looking to develop therapeutics that mimic the benefits of less tau by targeting factors that interact with it. One such candidate is the Src kinase fyn. Several years ago, researchers led by Ittner and Jürgen Götz, who is now at the University of Queensland in Brisbane, Australia, reported that tau targets fyn to the N-methyl-D-aspartic acid (NMDA) receptor, where it phosphorylates the 2b subunit. This strengthens the receptor’s interaction with PSD-95 and promotes Aβ-induced excitotoxicity at the synapse (Jul 2010 conference story on Ittner et al., 2010).  Roberson and colleagues found that fyn overexpression exacerbates AD-related seizures and cognitive impairment in amyloidogenic mice, and that engineering fyn/APP mice with a tau-deficient background mitigated these problems.

The Roberson lab presented several posters detailing their efforts to target tau-fyn interactions. In a high-throughput screen of 90,000 small molecules, Nick Cochran and colleagues found several dozen that blocked tau-fyn interaction. They plan to take candidates that look promising into cells and tweak them to make them more potent and specific. 

In related work, Pauleatha Diggs in the lab explored the role of phosphorylation in tau-fyn interactions. Dendritic tau becomes hyperphosphorylated at particular sites, and phosphorylation by microtubule-affinity-regulating kinase (MARK) correlates with localization of tau to dendrites. When the researchers pseudophosphorylated four MARK sites in tau’s microtubule-binding domains, the tau bound more tightly with fyn than did wild-type tau. These findings suggest that tau and fyn form a tight complex in dendrites. This would strengthen the rationale for blocking the tau-fyn association as a therapeutic approach.—Esther Landhuis

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  1. Emerging data from several groups demonstrating pro-convulsive effects of tau protein (Roberson et al., 2007; Roberson et al., 2011; DeVos et al., 2013; Holth et al., 2013) requires further in-depth analysis and careful interpretation in the context of the normal biology of neurons, as well as in the context of the mechanisms of neurodegenerative disease. It appears that we are looking at a new, exciting, and highly conserved neurobiological phenomenon, which is at work from the primitive neural ganglia of drosophila to the sophisticated mammalian nervous system. The fact that two fundamentally different Kv channel types (subunits), with physiologically distinct expression patterns (pre-synaptic terminals vs. dendritic, Kv1.1 and Kv4.2) and functional profiles (distinct activation and inactivation parameters) (Robertson, 1997; Trimmer and Rhodes, 2004), can be altered by tau in favor of neuronal hyperexcitability with epileptic activity suggests a key role played by tau in regulating global processes and mechanisms stabilizing neuronal networks. To appreciate fully the singularity of the phenotypes described by these recent papers, it is worth stressing that the deficit of the Kv1.1 sister channel subunit Kv1.2 has the opposite effects on neuronal excitability—neurons of Kv1.2 knockout mice reveal dampened excitability (Smart et al., 1998; Brew et al., 2007; Robbins and Tempel, 2012). The Identification of key molecular players that contribute to tau-driven, converging phenotypes, as the recent work suggests, could provide important clues into the evolutionary roots and potential relatedness of two prevalent and devastating disorders of the mind—epilepsy and Alzheimer’s disease. They also may provide avenues for the eventual use of some antiepileptic Kv channel enhancers (including some steroidal anti-inflammatory drugs cleaving the Kv β subunits) as palliative treatments for Alzheimer’s disease.

    References:

    . Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. J Neurophysiol. 2007 Sep;98(3):1501-25. Epub 2007 Jul 18 PubMed.

    . Antisense Reduction of Tau in Adult Mice Protects against Seizures. J Neurosci. 2013 Jul 31;33(31):12887-97. PubMed.

    . Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J Neurosci. 2013 Jan 23;33(4):1651-9. PubMed.

    . Kv1.1 and Kv1.2: similar channels, different seizure models. Epilepsia. 2012 Jun;53 Suppl 1:134-41. PubMed.

    . Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.

    . 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.

    . The real life of voltage-gated K+ channels: more than model behaviour. Trends Pharmacol Sci. 1997 Dec;18(12):474-83. PubMed.

    . Deletion of the K(V)1.1 potassium channel causes epilepsy in mice. Neuron. 1998 Apr;20(4):809-19. PubMed.

    . Localization of voltage-gated ion channels in mammalian brain. Annu Rev Physiol. 2004;66:477-519. PubMed.

References

Research Models Citations

  1. J20 (PDGF-APPSw,Ind)
  2. PDGF-APPSw,Ind (line J9)

News Citations

  1. Do "Silent" Seizures Cause Network Dysfunction in AD?
  2. APP Mice: Losing Tau Solves Their Memory Problems
  3. San Francisco: Is Tau Reduction a Good Thing?
  4. One Protein Fits All? Non-AD Epilepsy Models Thrive Sans Tau
  5. Honolulu: The Missing Link? Tau Mediates Aβ Toxicity at Synapse

Paper Citations

  1. . 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.
  2. . Antisense Reduction of Tau in Adult Mice Protects against Seizures. J Neurosci. 2013 Jul 31;33(31):12887-97. PubMed.
  3. . Dendritic patch-clamp recording. Nat Protoc. 2006;1(3):1235-47. PubMed.
  4. . Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction. Circ Res. 2005 Dec 9;97(12):1342-50. Epub 2005 Nov 17 PubMed.
  5. . Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. PubMed.

Further Reading

Papers

  1. . Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.
  2. . 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.
  3. . Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. PubMed.
  4. . The dendritic hypothesis for Alzheimer's disease pathophysiology. Brain Res Bull. 2014 Apr;103:18-28. Epub 2013 Dec 12 PubMed.