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Acta Neuropathologica

, Volume 130, Issue 3, pp 349–362 | Cite as

Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections

  • Michiyo Iba
  • Jennifer D. McBride
  • Jing L. Guo
  • Bin Zhang
  • John Q. Trojanowski
  • Virginia M.-Y. Lee
Original Paper

Abstract

Filamentous tau inclusions are hallmarks of Alzheimer’s disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed (Iba et al., J Neurosci 33:1024–1037, 2013) that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle-bearing neurons degenerated in the LC ipsilateral to the injection site starting 6 months post-injection, no neuron loss was seen in the contralateral LC wherein tangle-bearing neurons gradually cleared tau pathology by 6–12 months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread, this novel mouse model provides unique opportunities to elucidate mechanisms underlying the selective vulnerability of neurons to acquire tau pathology and succumb to or resist tau-mediated neurodegeneration.

Keywords

Transmission of misfolded tau Alzheimer’s disease Mouse models of tauopathies Locus coeruleus 

Notes

Acknowledgments

This work was supported by National Institutes of Health Grant AG17586 and the Marian S. Ware Alzheimer Program Cure Alzheimer’s Fund, the Karen Cohen Segal and Christopher S. Segal Alzheimer Drug Discovery Initiative Fund, the Paula C. Schmerler Fund for Alzheimer’s Research, the Barrist Neurodegenerative Disease Research Fund, the Eleanor Margaret Kurtz Endowed Fund, the Mary Rasmus Endowed Fund for Alzheimer’s Research, Gloria J. Miller, and Dr. Arthur Peck. We thank Joshua Daniels, Bryan Zoll and Susan Leight for their assistance in mouse husbandry, Martine White and Chris Chung for counting cell numbers, Theresa Schuck, John Robinson, and Kevin Raible for their technical assistance in immunohistochemistry, and Rui Tong for his computer expertise in constructing the heat maps.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animal were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

401_2015_1458_MOESM1_ESM.docx (4 mb)
Supplementary material 1 (DOCX 4123 kb)

References

  1. 1.
    Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, Parhizkar S, Ward MA, Cavallini A, Jackson S et al (2014) A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol 127:667–683. doi: 10.1007/s00401-014-1254-6 PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42:631–639CrossRefPubMedGoogle Scholar
  3. 3.
    Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450. doi: 10.1146/annurev.neuro.28.061604.135709 CrossRefPubMedGoogle Scholar
  4. 4.
    Aston-Jones G, Ennis M, Pieribone VA, Nickell WT, Shipley MT (1986) The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network. Science 234:734–737CrossRefPubMedGoogle Scholar
  5. 5.
    Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672. doi: 10.1038/nrn2194 CrossRefPubMedGoogle Scholar
  6. 6.
    Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev 42:33–84. doi: 10.1016/S0165-0173(03)00143-7 CrossRefPubMedGoogle Scholar
  7. 7.
    Bobinski M, Wegiel J, Tarnawski M, de Leon MJ, Reisberg B, Miller DC, Wisniewski HM (1998) Duration of neurofibrillary changes in the hippocampal pyramidal neurons. Brain Res 799:156–158 (pii:S0006-8993(98)00441-7) CrossRefPubMedGoogle Scholar
  8. 8.
    Boluda S, Iba M, Zhang B, Raible KM, Lee VM, Trojanowski JQ (2015) Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol 129:221–237. doi: 10.1007/s00401-014-1373-0 PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259CrossRefPubMedGoogle Scholar
  10. 10.
    Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181. doi: 10.1007/s00401-010-0789-4 CrossRefPubMedGoogle Scholar
  11. 11.
    Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. doi: 10.1097/NEN.0b013e318232a379 CrossRefPubMedGoogle Scholar
  12. 12.
    Brettschneider J, Del Tredici K, Lee VM, Trojanowski JQ (2015) Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci 16:109–120. doi: 10.1038/nrn3887 PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Carter ME, Yizhar O, Chikahisa S, Nguyen H, Adamantidis A, Nishino S, Deisseroth K, de Lecea L (2010) Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat Neurosci 13:1526–1533. doi: 10.1038/nn.2682 PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Cedarbaum JM, Aghajanian GK (1978) Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique. J Comp Neurol 178:1–16. doi: 10.1002/cne.901780102 CrossRefPubMedGoogle Scholar
  15. 15.
    Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Probst A, Winkler DT, Reichwald J, Staufenbiel M et al (2013) Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 110:9535–9540. doi: 10.1073/pnas.1301175110 PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913. doi: 10.1038/ncb1901 PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Clavier RM (1979) Afferent projections to the self-stimulation regions of the dorsal pons, including the locus coeruleus, in the rat as demonstrated by the horseradish peroxidase technique. Brain Res Bull 4:497–504CrossRefPubMedGoogle Scholar
  18. 18.
    de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA et al (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697. doi: 10.1016/j.neuron.2011.11.033 PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Foote SL, Bloom FE, Aston-Jones G (1983) Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev 63:844–914PubMedGoogle Scholar
  20. 20.
    Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852. doi: 10.1074/jbc.M808759200 PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Guo JL, Lee VM (2014) Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 20:130–138. doi: 10.1038/nm.3457 PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Guo JL, Lee VM (2013) Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau. FEBS Lett 587:717–723. doi: 10.1016/j.febslet.2013.01.051 PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Guo JL, Lee VM (2011) Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286:15317–15331. doi: 10.1074/jbc.M110.209296 PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Hurtado DE, Molina-Porcel L, Iba M, Aboagye AK, Paul SM, Trojanowski JQ, Lee VM (2010) Aβ accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model. Am J Pathol 177:1977–1988. doi: 10.2353/ajpath.2010.100346 PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM (2013) Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci 33:1024–1037. doi: 10.1523/JNEUROSCI.2642-12.2013 PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Irwin DJ, Cairns NJ, Grossman M, McMillan CT, Lee EB, Van Deerlin VM, Lee VM, Trojanowski JQ (2015) Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol 129:469–491. doi: 10.1007/s00401-014-1380-1 CrossRefPubMedGoogle Scholar
  27. 27.
    Kenessey A, Yen SH, Liu WK, Yang XR, Dunlop DS (1995) Detection of d-aspartate in tau proteins associated with Alzheimer paired helical filaments. Brain Res 675:183–189 (pii:0006-8993(95)00061-T) CrossRefPubMedGoogle Scholar
  28. 28.
    Kuchibhotla KV, Wegmann S, Kopeikina KJ, Hawkes J, Rudinskiy N, Andermann ML, Spires-Jones TL, Bacskai BJ, Hyman BT (2014) Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc Natl Acad Sci USA 111:510–514. doi: 10.1073/pnas.1318807111 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159. doi: 10.1146/annurev.neuro.24.1.1121 CrossRefPubMedGoogle Scholar
  30. 30.
    Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7:e31302. doi: 10.1371/journal.pone.0031302 PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Luppi PH, Aston-Jones G, Akaoka H, Chouvet G, Jouvet M (1995) Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin. Neuroscience 65:119–160CrossRefPubMedGoogle Scholar
  32. 32.
    Moore RY, Bloom FE (1979) Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu Rev Neurosci 2:113–168. doi: 10.1146/annurev.ne.02.030179.000553 CrossRefPubMedGoogle Scholar
  33. 33.
    Morgane PJ, Jacobs MS (1979) Raphe projections to the locus coeruleus in the rat. Brain Res Bull 4:519–534CrossRefPubMedGoogle Scholar
  34. 34.
    Morozova OA, March ZM, Robinson AS, Colby DW (2013) Conformational features of tau fibrils from Alzheimer’s disease brain are faithfully propagated by unmodified recombinant protein. Biochemistry 52:6960–6967. doi: 10.1021/bi400866w PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Morsch R, Simon W, Coleman PD (1999) Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 58:188–197CrossRefPubMedGoogle Scholar
  36. 36.
    Paxinos G, Franklin K (2003) The mouse brain in stereotaxic coordinates, 2nd edn. Academic, WalthamGoogle Scholar
  37. 37.
    Peeraer E, Bottelbergs A, Van Kolen K, Stancu IC, Vasconcelos B, Mahieu M, Duytschaever H, Ver Donck L, Torremans A, Sluydts E et al (2015) Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice. Neurobiol Dis 73:83–95. doi: 10.1016/j.nbd.2014.08.032 PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481. doi: 10.1126/science.1113694 PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Stancu IC, Vasconcelos B, Ris L, Wang P, Villers A, Peeraer E, Buist A, Terwel D, Baatsen P, Oyelami T et al (2015) Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. Acta Neuropathol 129:875–894. doi: 10.1007/s00401-015-1413-4 PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Van der Jeugd A, Hochgrafe K, Ahmed T, Decker JM, Sydow A, Hofmann A, Wu D, Messing L, Balschun D, D’Hooge R et al (2012) Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta Neuropathol 123:787–805. doi: 10.1007/s00401-012-0987-3 CrossRefPubMedGoogle Scholar
  41. 41.
    Wilcock GK, Esiri MM (1982) Plaques, tangles and dementia. A quantitative study. J Neurol Sci 56:343–356CrossRefPubMedGoogle Scholar
  42. 42.
    Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293:711–714. doi: 10.1126/science.1062382 CrossRefPubMedGoogle Scholar
  43. 43.
    Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351. doi: 10.1016/j.neuron.2007.01.010 CrossRefPubMedGoogle Scholar
  44. 44.
    Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AM, Xie SX, Ballatore C, Smith AB 3rd et al (2012) The microtubule-stabilizing agent, epothilone d, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci 32:3601–3611. doi: 10.1523/JNEUROSCI.4922-11.2012 PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Michiyo Iba
    • 1
  • Jennifer D. McBride
    • 1
  • Jing L. Guo
    • 1
  • Bin Zhang
    • 1
  • John Q. Trojanowski
    • 1
  • Virginia M.-Y. Lee
    • 1
  1. 1.Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease ResearchUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA

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