Making It Stick—Tau Toxicity Linked to Aggregation Propensity

Snarls of tau protein accumulate in Alzheimer’s disease and other dementias, but increasing evidence suggests that it is soluble tau that does the most harm. At the same time, new research indicates that the stickiness of tau, i.e., its ability to aggregate, may be essential to its toxicity. In today’s Journal of Neuroscience, researchers led by Eckhard and Eva-Maria Mandelkow at the Max Planck Unit for Structural Molecular Biology in Hamburg, Germany, describe divergent effects seen in two inducible tau mouse models. In one, tau lacked the ability to aggregate; in the other, it was prone to form clumps. Only the latter mouse developed synaptic damage and learning and memory defects. Switching off mutant tau expression allowed these mice to regrow synapses and reversed learning problems even though tangles persisted. This reinforces the idea that soluble tau harms synapses, and also lends hope to the idea that interfering with tau aggregation could treat early cognitive impairment. Yesterday, the American Academy of Neurology announced that the Mandelkows will receive the 2011 Potamkin prize for Research in Alzheimer’s, Pick’s, and Related Diseases for their studies of tau. They share the award with Dennis Dickson at the Mayo Clinic in Jacksonville, Florida (see ARF related news brief).

As is the case for Aβ, numerous studies now support the idea that oligomers of tau may be more toxic than large aggregates (see, e.g., Oddo et al., 2006; Marx, 2007; Berger et al., 2007; Brunden et al., 2008; Meraz-Rios et al., 2009). In fact, Karen Hsiao Ashe and colleagues at the University of Minnesota, Minneapolis, first showed that turning off tau expression in an inducible mouse model stops neuron loss and improves memory, even though neurofibrillary tangles persist (see ARF related news story on Santacruz et al., 2005). These findings generated interest in therapies targeting tau oligomers (see, e.g., ARF related news story).

More recently, Ashe and Dezhi Liao, also at the University of Minnesota, showed in an animal model that mutant human tau invades dendritic spines early in disease, leading first to synaptic defects and later to neurodegeneration (see ARF related news story on Hoover et al., 2010). In contrast, normal, non-aggregating tau only mildly affected synapses and caused no neurodegeneration. This is in keeping with the principle that aggregating tau is the toxic variety, Eckhard Mandelkow told ARF.

To investigate the effects of tau aggregation, the Mandelkows previously developed their “pro-aggregant” and “anti-aggregant” inducible tau mice (see ARF related news story on Mocanu et al., 2008). Pro-aggregant tau forms β-sheets, while anti-aggregant tau contains proline mutations preventing that.

In that work, the Mandelkows and colleagues reported that only the mice with sticky tau developed AD-like pathology, which included missorting, hyperphosphorylation, and aggregation of tau, as well as the loss of synapses and neurons. Mice with anti-aggregant tau only showed some tau missorting and mild synaptic effects, probably because excess tau clogs up microtubules and gets in the way of transport, Eva-Maria Mandelkow said. Moreover, in the mice with pro-aggregant tau, tangles contained both toxic transgenic tau and normal mouse tau. Switching off the transgene converted the tangles to containing pure mouse tau. This suggests that the human protein can shuttle in and out of aggregates and can poison normal tau (see ARF related news story on Clavaguera et al., 2009).

The current study examined the behavioral and synaptic effects. First authors Astrid Sydow in the Mandelkow lab and Ann Van der Jeugd in Rudi d'Hooge's lab at K.U. Leuven, Belgium, used 14-month-old mice in which tau was expressed for 10 months and then turned off for four. After 10 months, mice with the sticky tau learned poorly in the Morris water maze and fear conditioning tests. After four more months without mutant tau protein, their abilities bounced back to wild-type levels, although the number and size of neurofibrillary tangles in the hippocampus and cortex remained the same and the mice did not regain lost neurons. The authors traced this rebound to synapse recovery: After 10 months, mice with pro-aggregant tau had roughly one-third fewer synapses than control mice, but four months after switch-off, mice had recovered half of that deficit. This suggests that in the absence of tau expression, new synapses flourished. Correspondingly, collaborators Tariq Ahmed at K.U. Leuven and Christian Alzheimer (a relative of Alois) at the University of Erlangen-Nuremberg, Germany, found that long-term potentiation (LTP) in the hippocampal CA1 and CA3 regions was down in pro-aggregant tau mice, but recovered after the transgene was switched off. Conversely, in mice with anti-aggregant tau, LTP was enhanced in the CA1 region at 10 months of age.

These data imply that tau tangles by themselves are not toxic, which fits with previous findings from the Ashe group. The ability to aggregate, however, appears to be crucial to tau’s harmful effects, the Mandelkows said. Researchers led by Hilal Lashuel at École Polytechnique Fédérale de Lausanne, Switzerland, have also put forward this idea for Aβ, suggesting that it is the aggregation process itself that is toxic (see Jan et al., 2010 and Wogulis et al., 2005). One explanation for the tau findings would be that oligomers of the protein are poisoning synapses, as numerous studies have suggested before (reviewed in Sahara et al., 2008).

The Mandelkows propose an alternate hypothesis, namely that the presence of an aggregation-prone protein may strain the cell because cellular protein degradation mechanisms such as autophagy become overactive. Several studies support such an idea (see ARF related news story on Wang et al., 2009; ARF related news story on Dickey et al., 2007; and ARF related news story on Carrettiero et al., 2009).

Both mechanisms may be occurring, Lary Walker of Emory University in Atlanta, Georgia, told ARF. Walker is intrigued by the therapeutic implications of the findings. “This paper suggests that anything that can inhibit tau aggregation in vivo, such as a small molecule, might well work in improving cognitive function, even if the tangles themselves persist.”

“The paper is very solid,” wrote Marc Diamond of Washington University in St. Louis, Missouri, in an e-mail to ARF. “It adds to an existing body of work for tau and other toxic proteins (e.g., huntingtin), which demonstrates that neurotoxicity from a transgene can be reversed if the expression of the transgene is turned off.”

In unpublished work, Eva-Maria Mandelkow’s group found that human tau disappears from tangles in as little as four weeks after the transgene is switched off. This is important, she said, because it is the human amyloidogenic tau that damages synapses. Once the cells clear it, synapses recover. The Mandelkows hope that preventing tau aggregation might have the same beneficial effect.

“We are excited about [the therapeutic possibilities],” Eva-Maria Mandelkow said, adding that stimulating tau degradation or preventing aggregation could both be useful strategies. The group previously screened about 200,000 compounds (see Pickhardt et al., 2005 and Pickhardt et al., 2007) and are now testing some hits on the mice with pro-aggregant tau. “The principle is if you prevent β structure, then you can prevent disease,” Eckhard Mandelkow said.—Madolyn Bowman Rogers

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References

News Citations

  1. No Toxicity in Tau’s Tangles?
  2. San Diego: Tau Oligomer Antibodies Relieve Motor Deficits in Mice
  3. Tau’s Synaptic Hats: Regulating Activity, Disrupting Communication
  4. Tau Roundup: Inducible Mice Accentuate Aggregation and More
  5. Traveling Tau—A New Paradigm for Tau- and Other Proteinopathies?
  6. Lysosomes: Hotbeds Where Tau Oligomers Seed Aggregation?
  7. Therapeutic Takedown: Hsp90 Inhibitors Tackle Tau
  8. Garbage BAG2 Takes Out the Tau

Paper Citations

  1. Oddo S, Vasilevko V, Caccamo A, Kitazawa M, Cribbs DH, Laferla FM. Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem. 2006 Dec 22;281(51):39413-23. PubMed.
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  4. Brunden KR, Trojanowski JQ, Lee VM. Evidence that non-fibrillar tau causes pathology linked to neurodegeneration and behavioral impairments. J Alzheimers Dis. 2008 Aug;14(4):393-9. PubMed.
  5. Meraz-Ríos MA, Lira-De León KI, Campos-Peña V, De Anda-Hernández MA, Mena-López R. Tau oligomers and aggregation in Alzheimer's disease. J Neurochem. 2010 Mar;112(6):1353-67. PubMed.
  6. Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005 Jul 15;309(5733):476-81. PubMed.
  7. 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.
  8. Mocanu MM, Nissen A, Eckermann K, Khlistunova I, Biernat J, Drexler D, Petrova O, Schönig K, Bujard H, Mandelkow E, Zhou L, Rune G, Mandelkow EM. The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci. 2008 Jan 16;28(3):737-48. PubMed.
  9. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.
  10. Jan A, Adolfsson O, Allaman I, Buccarello AL, Magistretti PJ, Pfeifer A, Muhs A, Lashuel HA. Abeta42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Abeta42 species. J Biol Chem. 2011 Mar 11;286(10):8585-96. PubMed.
  11. Wogulis M, Wright S, Cunningham D, Chilcote T, Powell K, Rydel RE. Nucleation-dependent polymerization is an essential component of amyloid-mediated neuronal cell death. J Neurosci. 2005 Feb 2;25(5):1071-80. PubMed.
  12. Sahara N, Maeda S, Takashima A. Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration. Curr Alzheimer Res. 2008 Dec;5(6):591-8. PubMed.
  13. Wang Y, Martinez-Vicente M, Krüger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet. 2009 Nov 1;18(21):4153-70. PubMed.
  14. Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM, Dunmore J, Ash P, Shoraka S, Zlatkovic J, Eckman CB, Patterson C, Dickson DW, Nahman NS, Hutton M, Burrows F, Petrucelli L. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest. 2007 Mar;117(3):648-58. PubMed.
  15. Carrettiero DC, Hernandez I, Neveu P, Papagiannakopoulos T, Kosik KS. The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the microtubule. J Neurosci. 2009 Feb 18;29(7):2151-61. PubMed.
  16. Pickhardt M, Gazova Z, von Bergen M, Khlistunova I, Wang Y, Hascher A, Mandelkow EM, Biernat J, Mandelkow E. Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells. J Biol Chem. 2005 Feb 4;280(5):3628-35. PubMed.
  17. Pickhardt M, Larbig G, Khlistunova I, Coksezen A, Meyer B, Mandelkow EM, Schmidt B, Mandelkow E. Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of tau aggregation and toxicity in vitro and in cells. Biochemistry. 2007 Sep 4;46(35):10016-23. PubMed.

Other Citations

  1. ARF related news brief

Further Reading

Primary Papers

  1. Sydow A, Van der Jeugd A, Zheng F, Ahmed T, Balschun D, Petrova O, Drexler D, Zhou L, Rune G, Mandelkow E, D'Hooge R, Alzheimer C, Mandelkow EM. Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci. 2011 Feb 16;31(7):2511-25. PubMed.

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