Just as they have done for amyloid β and other proteins that form toxic aggregates, molecular biologists have turned their attention from large neurofibrillary tangles to smaller oligomeric forms of tau. One unanswered question is what drives these oligomers to form in the first place? A paper in the September 3 Journal of Clinical Investigation offers clues. Researchers led by senior author Chad Dickey at the University of South Florida, Tampa, found that a pair of chaperones yanks tau from the jaws of the proteasome. Alas, as they save it from degradation, they at the same time fold it into oligomeric conformations. Specifically, heat shock protein Hsp90 partners with the co-chaperone FK506 binding protein 51 kiloDaltons (FKBP51) to generate these potentially toxic forms of tau. While targeting heat shock proteins with inhibitors could have broad, unwanted side effects, blocking FKBP51 specifically could potentially be a tau-based therapy, Dickey suggested.

Tau predominantly exists bound to microtubules in the cell. Free tau is degraded in the proteasome, but Hsp90 and its cofactors including CHIP and FKBP51 rescue tau from this fate. (see ARF related news on Dickey et al., 2007 and Luo et al., 2007; Jinwal et al., 2010). Thus, turning off Hsp90 should force the cell to dismantle unneeded tau. Hsp90 inhibitors are under study in several trials for cancer, where the chaperone stabilizes undesirable oncoproteins. However, Dickey suspects that long-term use of Hsp90 inhibitors would be toxic in tauopathies, since the protein stabilizes other essential targets. In this study, his group turned to FKBP51 instead.

Initially, the authors wondered if FKBP51 levels changed in the case of aging or disease. First author Laura Blair and colleagues used microarrays to examine the gene’s expression in autopsy brain samples from neurologically healthy donors. They observed three to four times higher FKBP51 expression in the postcentral gyrus, the superior-frontal gyrus, hippocampus, and entorhinal cortex of older (age 60-99) brains compared to young (age 20-59). Expression of Hsp90 and its other partners, CHIP and FKBP52, decreased slightly.

In people with Alzheimer’s, FKBP51 expression topped that in age-matched healthy controls as well, and climbed even higher in people diagnosed with more advanced disease based on Braak staging. Levels of Hsp90 and the other co-chaperones in the AD brains equaled those in controls. The data suggested that FKBP51 could contribute to Alzheimer’s pathology, and encouraged the scientists to examine the protein further, Dickey said. He plans to examine FKBP51 expression in samples from people who died of frontotemporal dementia or progressive supranuclear palsy, two other tauopathies. Ben Wolozin of Boston University, who was not involved in the study, predicted FKBP51 would play a similar role in other tauopathies as it might in AD.

Dickey’s previous work showed that removing FKBP51 in vitro lowered tau levels, but the researchers wanted to test that concept in vivo. In FKBP51 knockout mice they observed reduced tau in the brain using immunohistochemical analysis of tissue sections and Western blotting of brain homogenates. Though the tau only dropped by about a third, a small effect, Dickey said, the results supported a role for FKBP51 in tau biology. Overexpression experiments hinted in the same direction. The researchers injected adeno-associated virus toting the FKBP51 gene into the hippocampi of rTg4510 transgenic mice, which harbor a human tauopathy gene with the proline-301-leucine mutation. Two months later, the neurons overexpressing FKBP51 contained more tau than neurons in control mice.

Blair and colleagues saw these increases with the T22 antibody, which is specific for oligomeric forms (see ARF related news and Lasagna-Reeves et al., 2012). The findings suggest that FKBP51 specifically promotes formation of tau oligomers. In-vitro data supported this idea. When the researchers incubated tau with FKBP51 and Hsp90 they observed an increase in T22 binding on dot blots, indicating the chaperones were reshaping tau into an oligomeric form. Circular dichroism and dynamic light scattering experiments confirmed that tau changed conformation in the presence of the two chaperones. This only occurred when both Hsp90 and FKBP51 were present, indicating the two work as a pair.

Co-author Rakez Kayed at the University of Texas Medical Branch, Galveston, developed the T22 antibody (see ARF related news). Though relatively new, “it seems like it works as advertised,” Dickey said. Kun Ping Lu of Beth Israel Deaconess Medical Center in Boston, who did not participate in the work, agreed there was no reason to doubt T22’s specificity. Wolozin commented that the T22 staining alone would not be fully convincing, but those results are strengthened by atomic force microscopy images showing tau oligomer particles.

If oligomeric tau rises in neurons overexpressing FKBP51, then what happens to tau tangles? The researchers found fewer of them. Moreover, tipping the balance from tangles to oligomers appeared to be neurotoxic. P301L tau transgenic mice injected with the viral FKBP51 gene possessed fewer tangles but also fewer hippocampal neurons, than control animals expressing green fluorescent protein. And in cultures of the mouse neuroblastoma cell line Neuro2a, co-transfection of tau and FKBP51 also promoted toxicity, compared to transfection with only tau or only FKBP51. These results led the authors to conclude that FKBP51 acts to turn tau into soluble oligomers, which damage neurons.

Dickey’s model suggests that in young people, FKBP51 levels remain low, and tau is properly degraded to prevent buildup and oligomerization. But with age, FKBP51 expression rises, and it seeks out its partner Hsp90. “It turns Hsp90 into a pro-tau toxicity machine, preserving tau and facilitating oligomer formation,” Dickey said. Increased FKBP51, combined with other hits such as stressors or AD risk genes, could lead to Alzheimer’s. People with naturally high levels of FKBP51 might be predisposed to develop AD, the authors predict.

“Although it remains controversial whether tangle formation is beneficial or toxic, increasingly, studies reveal that oligomeric tau species significantly contribute to toxicity,” commented Wenjie Luo of Weill Cornell Medical College in New York City in an email to Alzforum (see full comment below, and also ARF related news). Lu noted that the work also suggests that the non-phosphorylated form of tau participates in pathology, because FKBP51 acts on non-phosphorylated recombinant protein in vitro.

Dickey said that FKBP51 appears to do little beyond promoting tau stability and mice lacking the gene are fine. Lu added that to support the possibility of FKBP51 inhibitors as an Alzheimer’s drug, he would like to see the Dickey group cross tau transgenic mice with the FKBP51 knockout, which should reduce pathology. Dickey told Alzforum they are doing this now and expect data within the year. The researchers are also screening for potential FKBP51 inhibitors.—Amber Dance.

References:
Blair LJ, Nordhues BA, Hill SE, Scaglione KM, O'Leary JC, Fontaine SN, Breydo L, Zhang B, Li P, Wang L, Cotman C, Paulson HL, Muschol M, Uversky VN, Klengel T, Binder EB, Kayed R, Golde TE, Berchtold N, Dickey CA. Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Invest. 2013 Sep 3. [Epub ahead of print] Abstract

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Comments on News and Primary Papers

  1. The development of tau pathology likely undergoes the following process: tau protein accumulation, oligomerization, fibril and tangle formation. It is essential to identify the toxic species of tau and the factors regulating the formation of these toxic species. Tau protein is intrinsically unstable, rendering it a good substrate for the molecular chaperone Hsp90. Earlier studies from Dr. Dickey's and our group revealed that inhibiting Hsp90 disrupts the interaction between Hsp90 complex and tau, and induces tau degradation both in vitro and in vivo, suggesting a role of Hsp90 in maintaining tau pathology in AD. However it was unclear how Hsp90 complex achieved this. We speculated that, with assistance from different co-chaperones, Hsp90 actively participates in different stages of tau aggregation.

    This study from Dr. Dickey’s group demonstrates an essential role of FKBP51, a cochaperone of Hsp90, in tau aggregation during AD. By coordinating with the Hsp90 machinery, FKBP51 alters tau structure, prevents tau degradation, and promotes formation of tau oligomers. Although it remains controversial whether tangle formation is beneficial or toxic, increasingly, studies reveal that oligomeric tau species significantly contribute to toxicity. It is now necessary to identify the specific toxic oligomer(s) using more advanced biochemical or cell biology approaches in order to confirm and further dissect the role of Hsp90 machinery in facilitating toxicity.

    Another interesting open question is whether the Hsp90 machinery contributes to tau spreading in brain. These efforts will eventually help the development of AD-related therapeutic tools that inhibit Hsp90 activity or reduc the levels of its cochaperones like FKBP51.

    View all comments by Wenjie Luo

References

News Citations

  1. Therapeutic Takedown: Hsp90 Inhibitors Tackle Tau
  2. San Diego: Tau Oligomer Antibodies Relieve Motor Deficits in Mice
  3. Chicago: Tau and α-Synuclein Oligomers Follow Aβ Footsteps

Paper Citations

  1. . The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest. 2007 Mar;117(3):648-58. PubMed.
  2. . Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc Natl Acad Sci U S A. 2007 May 29;104(22):9511-6. PubMed.
  3. . The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules. J Neurosci. 2010 Jan 13;30(2):591-9. PubMed.
  4. . Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. FASEB J. 2012 Jan 17; PubMed.
  5. . Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Invest. 2013 Oct 1;123(10):4158-69. PubMed.

Other Citations

  1. rTg4510

Further Reading

Papers

  1. . FKBP51 and FKBP52 in signaling and disease. Trends Endocrinol Metab. 2011 Dec;22(12):481-90. PubMed.
  2. . FKBP immunophilins and Alzheimer's disease: a chaperoned affair. J Biosci. 2011 Aug;36(3):493-8. PubMed.
  3. . Bending tau into shape: the emerging role of peptidyl-prolyl isomerases in tauopathies. Mol Neurobiol. 2011 Aug;44(1):65-70. PubMed.
  4. . Hsp70 ATPase Modulators as Therapeutics for Alzheimer's and other Neurodegenerative Diseases. Mol Cell Pharmacol. 2010 Jan 1;2(2):43-46. PubMed.
  5. . Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Invest. 2013 Oct 1;123(10):4158-69. PubMed.

Primary Papers

  1. . Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Invest. 2013 Oct 1;123(10):4158-69. PubMed.