02 Aug 2013

Minimizing tau in adult mice reins in toxin-induced seizures, report scientists led by Timothy Miller, Washington University in St. Louis, Missouri, in collaboration with David Holtzman and John Cirrito. The results, outlined in the July 31 Journal of Neuroscience, suggest that reducing tau could benefit people with tau-related disorders marked by hyperactivity, such Alzheimer's disease (AD), wrote the authors. The study moves the field a critical step closer to tau therapy, commented Lars Ittner, University of New South Wales, Sydney, who was not involved in the study.

Mounting evidence suggests that tau plays a key role in neuronal hyperexcitability. For example, knocking out the protein protects mice against epilepsy-like activity (see ARF related news and ARF related news). Halving the amount of normal tau also protects hAPP mouse neurons against overexcitation brought on by Aβ (see ARF related news story), and tau seems to mediate Aβ's excitotoxicity at the synapse (see ARF related news story on Ittner et al., 2010). However, since these genetic models lack tau from birth, researchers wondered if compensatory mechanisms during development explained the protection from seizures. Would silencing tau in adult mice have the same effects?

To address this, first author Sarah DeVos and colleagues delivered anti-sense oligonucleotides (ASOs) developed by Isis Pharmaceuticals, Carlsbad, California, directly to the central nervous system (CNS) to knock down tau expression in adult wild-type mice. One month of treatment docked expression of endogenous tau mRNA and protein by more than 80 percent. The work was a collaboration with Isis.

The treated mice behaved as usual, with normal cognition and motor behavior. However, the oligonucleotides diminished seizures that were induced by intraperitoneal pentylenetetrazole (PTZ) or picrotoxin delivered directly to the hippocampus. These poisons evoke focal and global seizures, respectively. The strength of the seizures strongly correlated with levels of tau, such that less tau meant lower spike frequencies and weaker seizures. Mice with the least tau also took the longest time to reach maximum seizures induced by PTZ. Interestingly, the association between seizures and tau persisted in mice not treated with an ASO, suggesting that even just higher basal levels of the protein predispose neurons to hyperexcitability. This hints that levels of tau could predict susceptibility to seizures in people, suggested Miller.

"These important findings strongly support our view that reducing tau is a potentially viable therapeutic strategy, not only for AD but also for related tauopathies and other disorders associated with aberrant neuronal network activity," said Lennart Mucke, Gladstone Institute of Neurological Disease, San Francisco, California. Mucke said that although ASOs could be developed into a human therapy in principle, a small molecule approach would be easier to administer long-term to elderly people. Miller's group recently reported that an ASO against mutant superoxide dismutase 1, which causes a rare form of amyotrophic lateral sclerosis, appeared safe when delivered directly to the CNS through intrathecal infusion in a Phase 1 trial (see Miller et al., 2013). Mucke and others are searching for small molecule compounds that can suppress tau, and anti-tau immunotherapy is an active area of research (see ARF related series).

Ittner said more research should be done to examine tau's relationship to hyperexcitability in AD mouse models and other animal models of disease. Universal knockdown could be harder to achieve in larger brains, he pointed out, which means the strategy may not work well in humans. Miller next plans to look at PSAPP mice and strains that express human tau.

The implications of these results extend beyond therapies to the basic biology of tau, suggested David Sanders, also at WashU, who was not involved in this study. Sanders works in the lab of Marc Diamond, who studies propagation of tau among cells in the brain. Given that a tight correlation exists between tau levels and seizures on a short time scale, he doubts the association could be due to tau's known intraneuronal function of stabilizing microtubules. "The findings suggest to me that tau, possibly an extracellular form, plays a role in neuronal signaling," he said. "I suspect that in upcoming years additional functions will be attributed to tau that might explain this correlation between seizure severity and tau levels."

"We are very interested in the concept of extracellular versus intracellular tau, and the physiological roles each may play," wrote Miller to Alzforum in an email. He explained that the ASOs used in the current experiment reduce both forms of the protein. He and his colleagues are currently running experiments to try and parse the potential roles for each.—Gwyneth Dickey Zakaib

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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.
Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K, Ostrow LW, Schoenfeld D, Macklin EA, Norris DA, Manousakis G, Crisp M, Smith R, Bennett CF, Bishop KM, Cudkowicz ME. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013 May;12(5):435-42. Epub 2013 Mar 29 PubMed.

In Adult Mice, Reduced Tau Quiets Agitated Neurons

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