One Protein Fits All? Non-AD Epilepsy Models Thrive Sans Tau

Having less tau calms overactive neuronal networks and curbs cognitive impairment in mouse models of Alzheimer’s disease. Now, a study in the January 23 Journal of Neuroscience extends the benefits of reducing the protein to mouse and fly epilepsy models whose Aβ levels and cognition are normal. “In two different nervous system models, losing tau rescues a hyperexcitability phenotype,” said senior investigator Jeffrey Noebels of Baylor College of Medicine in Houston, Texas. Hypothetically, the findings broaden the therapeutic potential of lowering tau to non-AD settings. Some scientists cautioned that more mechanistic insight into how tau actually relieves seizures is needed.

Conceptually, epilepsy and Alzheimer’s appear to be opposing disorders—the former characterized by network hyperactivity; the latter, neuronal dysfunction and demise. Yet some scientists now wonder if the two diseases are more similar than previously recognized. “Seizures can kill neurons. They can change synaptic plasticity and synaptic strength, and cause long-term depression,” Noebels told Alzforum. And on the flipside, as cellular networks degrade in neurodegenerative disease, “depending on which cells die first, you might go through a period where the entire network is hyperexcitable.” This is the case if inhibitory neurons die before excitatory ones.

Hints of a link between AD and epilepsy piqued Noebels’ attention years ago when he received a phone call from Lennart Mucke at the Gladstone Institute of Neurological Disease in San Francisco. Mucke suspected that his J20 mice—a transgenic strain that develops Aβ pathology and memory loss from amyloid precursor protein (APP) overexpression—were having spontaneous seizures. He asked Noebels, an epileptologist, to have a look at the mice. Indeed, the animals had “incredibly striking, synchronous epileptic discharges,” Noebels said. “But they were not jerking around the way people might think. They were having ‘silent seizures’” (see ARF related news story on Palop et al., 2007). Moreover, J20 mice with tau levels halved had fewer seizures (ARF related news story on Roberson et al., 2007). Other AD transgenic strains also exhibit spontaneous seizures and reap similar benefits from tau reduction (see ARF related news story on Minkeviciene et al., 2009; ARF related news story on Roberson et al., 2011; Andrews-Zwilling et al., 2010; Hunter et al., 2012).

In the current study, first author Jerrah Holth and colleagues asked if removing tau might also dampen hyperexcitability in a seizure model that has nothing to do with Aβ. To address the question, the researchers crossed tau knockouts with Kcna1-/- mice. These mice develop enlarged brains, suffer severe seizures, and die early because they lack a critical potassium channel, but they have normal levels of brain Aβ, tau, and phospho-tau. Using in-vivo video electroencephalography (EEG) to monitor brain activity in freely moving animals, Holth and colleagues found that double knockouts fared much better than their Kcna1-/- littermates. Instead of the usual 10 to 15 seizures a day, Kcna1 knockout mice lacking tau had virtually none. They lived longer, too. Typically, only 30 percent of Kcna1-/- mice survive to 10 weeks of age. However, loss of one tau allele doubled their longevity, and losing both boosted lifespan even further, with 74 percent of tau/Kcna1 knockouts making it to 10 weeks. Furthermore, tau reduction prevented the hippocampi and forebrains of Kcna1 knockout mice from growing abnormally large.

Strengthening the case for tau reduction being protective, the researchers found similar benefits in “bang-sensitive” Drosophila mutants. These flies shake their legs in a characteristic, repetitive pattern because of membrane hyperexcitability caused by ion channel defects. “When you fill a test tube with these flies and bang it against something, most will drop to the bottom of the tube and start writhing and shaking,” Noebels said. However, when his team reduced tau levels, fewer flies behaved that way. The researchers saw this in two different bang-sensitive fly mutants.

“I think this is a very interesting and important study,” said Yadong Huang of the Gladstone Institute of Neurological Disease in San Francisco. “It demonstrates that tau plays a general role in regulating intrinsic network hyperactivity, independent of Aβ overexpression.” He and others praised the study’s use of a non-pharmacologic seizure model, unlike prior tau-reduction studies, which induced seizures in mice using kainic acid.

Research has linked AD to epilepsy in people as well. Spontaneous seizures have been reported in AD patients (see Imfeld et al., 2012; Scharfman, 2012), especially those with early onset familial forms (Cabrejo et al., 2006; Snider et al., 2005). Some anticonvulsant epilepsy drugs relieve network hyperactivity and improve memory in mild AD patients (ARF related news story), and in AD transgenic mice (ARF related news story).

Curiously, the benefits of tau removal seem to only show up in pathological conditions. Tau knockout mice look normal overall, though some develop subtle cognitive and motor defects (Morris et al., 2013), or parkinsonism symptoms as they age (Lei et al., 2012).

Though the current study conceptually broadens the potential therapeutic reach of tau reduction to epilepsy and other non-AD conditions, scientists called for more mechanistic insight before working on treatment approaches. “We need to understand how [tau] does what it does when preventing these seizures. Only then can we think about developing a treatment, which might not target tau itself, but its mechanism,” said Lars Ittner of the University of Sydney, Australia. Ittner discovered that tau mediates Aβ toxicity by targeting the Src kinase Fyn to NMDA receptors at synapses (ARF related news story on Ittner et al., 2010). Noebels agrees. “We need to learn a lot more about tau biology," he said. "For instance, where is it having effects on membrane excitability—inside the cell, or once it is released extracellularly? In which cellular compartments is tau controlling neuronal excitability?” Noebels noted that tau resides mainly in axons but can move elsewhere when hyperphosphorylated.

His lab currently studies whether lowering tau can rescue already established seizure disorders. Other scientists are also starting to explore whether epilepsy may contribute to other tauopathies, such as frontotemporal dementia.—Esther Landhuis

Comments

  1. The new data from Jeff Noebels' lab convincingly show that tau reduction decreases seizures in Kcna1 knockout mice and bang-sensitive flies, which undergo a type of paralysis/seizure when shaken. We and others have previously shown that reducing tau or expressing a truncated form of tau reduces seizure susceptibility, both in the absence and presence of Aβ. In their study, Holth and colleagues find (as we did) a dosage effect for tau, underscoring the validity of a therapeutic approach aimed at reducing tau levels in order to suppress network hyperexcitability. The majority of the published studies report no neurological defects in mice lacking tau, and as the authors of this nice study conclude, there are potential "therapeutic benefits of decreasing tau at an early stage of epileptogenesis."

    View all comments by Jürgen Götz

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References

News Citations

  1. Do "Silent" Seizures Cause Network Dysfunction in AD?
  2. APP Mice: Losing Tau Solves Their Memory Problems
  3. The Many Misdeeds of Aβ—Seizures and Axonal Transport Interference
  4. Tau’s Synaptic Hats: Regulating Activity, Disrupting Communication
  5. Epilepsy Drug Calms the Hippocampus, Aids Memory
  6. Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice
  7. Honolulu: The Missing Link? Tau Mediates Aβ Toxicity at Synapse

Paper Citations

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan TX, Chen L, Huang Y. Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010 Oct 13;30(41):13707-17. PubMed.
  6. Lalonde R, Dumont M, Staufenbiel M, Strazielle C. Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen. Behav Brain Res. 2005 Feb 10;157(1):91-8. PubMed.
  7. Imfeld P, Bodmer M, Schuerch M, Jick SS, Meier CR. Seizures in patients with Alzheimer's disease or vascular dementia: A population-based nested case-control analysis. Epilepsia. 2012 Dec 6; PubMed.
  8. Scharfman HE. "Untangling" Alzheimer's disease and epilepsy. Epilepsy Curr. 2012 Sep;12(5):178-83. PubMed.
  9. Cabrejo L, Guyant-Maréchal L, Laquerrière A, Vercelletto M, De la Fournière F, Thomas-Antérion C, Verny C, Letournel F, Pasquier F, Vital A, Checler F, Frebourg T, Campion D, Hannequin D. Phenotype associated with APP duplication in five families. Brain. 2006 Nov;129(Pt 11):2966-76. Epub 2006 Sep 7 PubMed.
  10. Snider BJ, Norton J, Coats MA, Chakraverty S, Hou CE, Jervis R, Lendon CL, Goate AM, McKeel DW Jr, Morris JC. Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol. 2005 Dec;62(12):1821-30. PubMed.
  11. Morris M, Hamto P, Adame A, Devidze N, Masliah E, Mucke L. Age-appropriate cognition and subtle dopamine-independent motor deficits in aged Tau knockout mice. Neurobiol Aging. 2013 Jun;34(6):1523-9. PubMed.
  12. Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012 Feb;18(2):291-5. PubMed.
  13. 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.

Other Citations

  1. J20 mice

Further Reading

Papers

  1. 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.
  2. 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.
  3. 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.

Primary Papers

  1. Holth JK, Bomben VC, Reed JG, Inoue T, Younkin L, Younkin SG, Pautler RG, Botas J, Noebels JL. Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J Neurosci. 2013 Jan 23;33(4):1651-9. PubMed.

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