Grow a Spine—Researchers Explain Brain Boost in Tauopathy Mice

It’s become conventional wisdom in Alzheimerology that tau pathology tends to track with mental decline in people with Alzheimer’s dementia, yet several years ago scientists found, to their surprise, that certain tauopathy mice actually have sharper cognition than wild-type mice early in life, before cognition tanks later on. Now, a study in the December 7 Journal of Neuroscience suggests that clues to this conundrum lie in dendritic spines. Fred Van Leuven and colleagues at the University of Leuven in Belgium report that young, brainy tau P301L mice have faster-maturing, longer spines than older siblings whose cognition is slipping. The older tau mice have stubby spines and sprout more of them, relative to control mice with normal tau. In addition, biochemical and immunohistochemical experiments help bolster the notion that tau’s physiological actions differ widely from its pathological doings.

Transgenic mice expressing P301L mutant human tau develop neurofibrillary tangles and motor problems, and most die before 10 months of age (Terwel et al., 2005). Curiously, though, in their youth (eight to 10 weeks of age), these same mice have increased long-term potentiation in the dentate gyrus and outperform wild-type littermates in a test of object recognition memory (ARF related news story on Boekhoorn et al., 2006). “It was a surprise that mutant tau could actually be beneficial,” Van Leuven said.

To probe the underlying mechanism, his team looked at what tau was doing to dendritic spines. First author Anna Kremer and colleagues crossed tau P301L mice—as well as the tau 4R strain expressing wild-type human tau at similar levels—with yellow fluorescent protein (YFP) mice to visualize axons, dendrites, and dendritic spines in vivo in bigenic progeny. Using confocal microscopy, the researchers imaged four brain areas affected by tauopathy and AD—the stratum, radiatum, and stratum oriens in the hippocampus, and cortical layer III above the striatum and above the hippocampus. They did so in young (one- to two-month-old) and adult (seven- to eight-month-old) mice. They measured the spine density, spine length, and spine maturation index, the last being the ratio of mushroom spines—which have mature, functional synapses—to all other spine types.

Analyzing nearly 58,000 spines in total for 20 mice, Kremer and colleagues found that, relative to YFP-only controls, young tau P301L mice sprouted normal numbers of spines, but an unusually high proportion of them were mature. In adult P301L transgenics, maturation index and spine length returned back to control levels, yet spine density remained high. The team saw similar effects in adult tau 4R mice, suggesting that wild-type and mutant tau may affect spine formation and morphology in comparable ways.

The researchers analyzed tau P301L and wild-type mouse brain for biochemical markers that could explain how tau proteins drive spine changes. They found both human P301L tau and endogenous mouse tau in synaptosomes, as judged by Western blot. However, immunohistochemistry using a variety of methods failed to detect appreciable amounts of mouse tau in dendritic spines; only human transgenic tau was there. This suggests that “tau’s actions in physiological conditions are quite different from its actions in pathological conditions,” Van Leuven said.

Jochen Herms of Ludwig-Maximilians University in Munich, Germany, pointed out, as did the authors, that it is possible that spine changes could result not only from dendritic pathology, but also from axonal signals. Axonal pathology has been shown to cause secondary spine loss in other tau-overexpressing transgenic mice, Herms noted in an e-mail to ARF. Tau is predominantly an axonal protein (see Hoover et al., 2010; Zempel et al., 2010), only moving into soma or dendrites when abnormally phosphorylated (see ARF related news story).

The mechanism behind the accelerated spine maturation in young tau P301L mice remains unknown. Dezhi Liao of the University of Minnesota, Minneapolis, speculated the enhancement could be due to compensation effects. Liao and others have shown that spine density and maturation goes up when AMPA receptor activity is blocked in cultured neurons, for instance (Liao et al., 1999; O’Brien et al., 1998).—Esther Landhuis

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References

News Citations

  1. Mutant Tau Sharpens Wits of Young Mice
  2. Time to Take the "Phospho" out of Tau?

Paper Citations

  1. Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, Van Leuven F. Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem. 2005 Feb 4;280(5):3963-73. PubMed.
  2. Boekhoorn K, Terwel D, Biemans B, Borghgraef P, Wiegert O, Ramakers GJ, de Vos K, Krugers H, Tomiyama T, Mori H, Joels M, Van Leuven F, Lucassen PJ. Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci. 2006 Mar 29;26(13):3514-23. PubMed.
  3. 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.
  4. Zempel H, Thies E, Mandelkow E, Mandelkow EM. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci. 2010 Sep 8;30(36):11938-50. PubMed.
  5. Liao D, Zhang X, O'Brien R, Ehlers MD, Huganir RL. Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons. Nat Neurosci. 1999 Jan;2(1):37-43. PubMed.
  6. O'Brien RJ, Kamboj S, Ehlers MD, Rosen KR, Fischbach GD, Huganir RL. Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron. 1998 Nov;21(5):1067-78. PubMed.

Other Citations

  1. tau P301L mice

Further Reading

Papers

  1. Boekhoorn K, Terwel D, Biemans B, Borghgraef P, Wiegert O, Ramakers GJ, de Vos K, Krugers H, Tomiyama T, Mori H, Joels M, Van Leuven F, Lucassen PJ. Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci. 2006 Mar 29;26(13):3514-23. 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. 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.

Primary Papers

  1. Kremer A, Maurin H, Demedts D, Devijver H, Borghgraef P, Van Leuven F. Early improved and late defective cognition is reflected by dendritic spines in Tau.P301L mice. J Neurosci. 2011 Dec 7;31(49):18036-47. PubMed.

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