Acta Neuropathologica

, Volume 136, Issue 1, pp 69–87 | Cite as

Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders

  • Brian Spencer
  • Sven Brüschweiler
  • Marco Sealey-Cardona
  • Edward Rockenstein
  • Anthony Adame
  • Jazmin Florio
  • Michael Mante
  • Ivy Trinh
  • Robert A. Rissman
  • Robert Konrat
  • Eliezer Masliah
Original Paper


Alzheimer’s disease (AD) is the most common form of dementia in the elderly affecting more than 5 million people in the U.S. AD is characterized by the accumulation of β-amyloid (Aβ) and Tau in the brain, and is manifested by severe impairments in memory and cognition. Therefore, removing tau pathology has become one of the main therapeutic goals for the treatment of AD. Tau (tubulin-associated unit) is a major neuronal cytoskeletal protein found in the CNS encoded by the gene MAPT. Alternative splicing generates two major isoforms of tau containing either 3 or 4 repeat (R) segments. These 3R or 4RTau species are differentially expressed in neurodegenerative diseases. Previous studies have been focused on reducing Tau accumulation with antibodies against total Tau, 4RTau or phosphorylated isoforms. Here, we developed a brain penetrating, single chain antibody that specifically recognizes a pathogenic 3RTau. This single chain antibody was modified by the addition of a fragment of the apoB protein to facilitate trafficking into the brain, once in the CNS these antibody fragments reduced the accumulation of 3RTau and related deficits in a transgenic mouse model of tauopathy. NMR studies showed that the single chain antibody recognized an epitope at aa 40–62 of 3RTau. This single chain antibody reduced 3RTau transmission and facilitated the clearance of Tau via the endosomal–lysosomal pathway. Together, these results suggest that targeting 3RTau with highly specific, brain penetrating, single chain antibodies might be of potential value for the treatment of tauopathies such as Pick’s Disease.


Tauopathy Pick’s disease Immunotherapy Alzheimer’s disease 



Supported by NIH grants AG5131, AG018440, AG051839. HEK293 antibody production was performed by the VBCF Protein Technologies Facility (


  1. 1.
    Adams SJ, DeTure MA, McBride M, Dickson DW, Petrucelli L (2010) Three repeat isoforms of tau inhibit assembly of four repeat tau filaments. PLoS One 5:e10810. PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Ahmad ZA, Yeap SK, Ali AM, Ho WY, Alitheen NB, Hamid M (2012) scFv antibody: principles and clinical application. Clin Dev Immunol 2012:980250. PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Alzheimer’s Association (2015) Latest facts and figures reportGoogle Scholar
  4. 4.
    Andreadis A, Brown WM, Kosik KS (1992) Structure and novel exons of the human tau gene. Biochemistry 31:10626–10633PubMedCrossRefGoogle Scholar
  5. 5.
    Arendt T, Stieler JT, Holzer M (2016) Tau and tauopathies. Brain Res Bull 126:238–292. PubMedCrossRefGoogle Scholar
  6. 6.
    Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci 27:9115–9129. PubMedCrossRefGoogle Scholar
  7. 7.
    Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672. PubMedCrossRefGoogle Scholar
  8. 8.
    Boado RJ, Lu JZ, Hui EK, Sumbria RK, Pardridge WM (2013) Pharmacokinetics and brain uptake in the rhesus monkey of a fusion protein of arylsulfatase a and a monoclonal antibody against the human insulin receptor. Biotechnol Bioeng 110:1456–1465. PubMedCrossRefGoogle Scholar
  9. 9.
    Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM (2011) Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem 118:658–667. PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Braczynski AK, Schulz JB, Bach JP (2017) Vaccination strategies in tauopathies and synucleinopathies. J Neurochem 143:467–488. PubMedCrossRefGoogle Scholar
  11. 11.
    Bright J, Hussain S, Dang V, Wright S, Cooper B, Byun T, Ramos C, Singh A, Parry G, Stagliano N et al (2015) Human secreted tau increases amyloid-beta production. Neurobiol Aging 36:693–709. PubMedCrossRefGoogle Scholar
  12. 12.
    Caillet-Boudin ML, Buee L, Sergeant N, Lefebvre B (2015) Regulation of human MAPT gene expression. Molecular Neurodegener 10:28. CrossRefGoogle Scholar
  13. 13.
    Canu N, Dus L, Barbato C, Ciotti MT, Brancolini C, Rinaldi AM, Novak M, Cattaneo A, Bradbury A, Calissano P (1998) Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis. J Neurosci 18:7061–7074PubMedCrossRefGoogle Scholar
  14. 14.
    Collin L, Bohrmann B, Gopfert U, Oroszlan-Szovik K, Ozmen L, Gruninger F (2014) Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain 137:2834–2846. PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Congdon EE, Lin Y, Rajamohamedsait HB, Shamir DB, Krishnaswamy S, Rajamohamedsait WJ, Rasool S, Gonzalez V, Levenga J, Gu J et al (2016) Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy. Mol Neurodegener 11:62. PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, Wilcock DM, Lynch JR, Laskowitz DT (2010) Loss of tau elicits axonal degeneration in a mouse model of Alzheimer’s disease. Neuroscience 169:516–531. PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP (2001) Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci 114:1179–1187PubMedGoogle Scholar
  18. 18.
    De Strooper B, Karran E (2016) The Cellular Phase of Alzheimer’s Disease. Cell 164:603–615. PubMedCrossRefGoogle Scholar
  19. 19.
    del Alonso CA, Iqbal K (2005) Tau-induced neurodegeneration: a clue to its mechanism. J Alzheimers Dis 8:223–226CrossRefGoogle Scholar
  20. 20.
    Delaglio F, Grzesiek S, Vuister GW, Zhu G, Pfeifer J, Bax A (1995) NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J Biomol NMR 6:277–293PubMedCrossRefGoogle Scholar
  21. 21.
    Dickson DW, Kouri N, Murray ME, Josephs KA (2011) Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau). J Mol Neurosci 45:384–389. PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Dixit R, Ross JL, Goldman YE, Holzbaur EL (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319:1086–1089. PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Encalada SE, Goldstein LS (2014) Biophysical challenges to axonal transport: motor-cargo deficiencies and neurodegeneration. Annu Rev Biophys 43:141–169. PubMedCrossRefGoogle Scholar
  24. 24.
    Ferrer I, Lopez-Gonzalez I, Carmona M, Arregui L, Dalfo E, Torrejon-Escribano B, Diehl R, Kovacs GG (2014) Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. J Neuropathol Exp Neurol 73:81–97. PubMedCrossRefGoogle Scholar
  25. 25.
    Forrest SL, Kril JJ, Stevens CH, Kwok JB, Hallupp M, Kim WS, Huang Y, McGinley CV, Werka H, Kiernan MC et al (2018) Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain 141:521–534. PubMedCrossRefGoogle Scholar
  26. 26.
    Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N et al (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A 100:10032–10037. PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Gao Y, Tan L, Yu JT, Tan L (2017) Tau in Alzheimer’s disease: mechanisms and therapeutic strategies. Curr Alzheimer Res. PubMedCrossRefGoogle Scholar
  28. 28.
    Goedert M, Jakes R (1990) Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J 9:4225–4230PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–526PubMedCrossRefGoogle Scholar
  30. 30.
    Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133:665–704. PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112. PubMedCrossRefGoogle Scholar
  32. 32.
    Habib A, Sawmiller D, Li S, Xiang Y, Rongo D, Tian J, Hou H, Zeng J, Smith A, Fan S et al (2017) LISPRO mitigates beta-amyloid and associated pathologies in Alzheimer’s mice. Cell Death Dis 8:e2880. PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, Sato-Yoshitake R, Takei Y, Noda T, Hirokawa N (1994) Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369:488–491. PubMedCrossRefGoogle Scholar
  34. 34.
    Higuchi M, Ishihara T, Zhang B, Hong M, Andreadis A, Trojanowski J, Lee VM (2002) Transgenic mouse model of tauopathies with glial pathology and nervous system degeneration. Neuron 35:433–446PubMedCrossRefGoogle Scholar
  35. 35.
    Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A et al (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282:1914–1917PubMedCrossRefGoogle Scholar
  36. 36.
    Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705. PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Ikegami S, Harada A, Hirokawa N (2000) Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett 279:129–132PubMedCrossRefGoogle Scholar
  38. 38.
    Ising C, Gallardo G, Leyns CEG, Wong CH, Stewart F, Koscal LJ, Roh J, Robinson GO, Remolina Serrano J, Holtzman DM (2017) AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy. J Exp Med 214:1227–1238. PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Israel EJ, Patel VK, Taylor SF, Marshak-Rothstein A, Simister NE (1995) Requirement for a beta 2-microglobulin-associated Fc receptor for acquisition of maternal IgG by fetal and neonatal mice. J Immunol 154:6246–6251PubMedGoogle Scholar
  40. 40.
    Israel EJ, Taylor S, Wu Z, Mizoguchi E, Blumberg RS, Bhan A, Simister NE (1997) Expression of the neonatal Fc receptor, FcRn, on human intestinal epithelial cells. Immunology 92:69–74PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ittner A, Bertz J, Suh LS, Stevens CH, Gotz J, Ittner LM (2015) Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice. J Neurochem 132:135–145. PubMedCrossRefGoogle Scholar
  42. 42.
    Jicha GA, Bowser R, Kazam IG, Davies P (1997) Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 48:128–132PubMedCrossRefGoogle Scholar
  43. 43.
    Jones NH, Clabby ML, Dialynas DP, Huang HJ, Herzenberg LA, Strominger JL (1986) Isolation of complementary DNA clones encoding the human lymphocyte glycoprotein T1/Leu-1. Nature 323:346–349PubMedCrossRefGoogle Scholar
  44. 44.
    Kanaan NM, Morfini G, Pigino G, LaPointe NE, Andreadis A, Song Y, Leitman E, Binder LI, Brady ST (2012) Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. Neurobiol Aging 33(826):e815–e830. CrossRefGoogle Scholar
  45. 45.
    Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M (2014) First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 6:44. PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kontsekova E, Zilka N, Kovacech B, Skrabana R, Novak M (2014) Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res Ther 6:45. PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kosik KS, Orecchio LD, Bakalis S, Neve RL (1989) Developmentally regulated expression of specific tau sequences. Neuron 2:1389–1397PubMedCrossRefGoogle Scholar
  48. 48.
    Kovacs GG (2015) Invited review: neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 41:3–23. PubMedCrossRefGoogle Scholar
  49. 49.
    Krishnaswamy S, Lin Y, Rajamohamedsait WJ, Rajamohamedsait HB, Krishnamurthy P, Sigurdsson EM (2014) Antibody-derived in vivo imaging of tau pathology. J Neurosci 34:16835–16850. PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Lacovich V, Espindola SL, Alloatti M, Pozo Devoto V, Cromberg LE, Carna ME, Forte G, Gallo JM, Bruno L, Stokin GB et al (2017) Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons. J Neurosci 37:58–69. PubMedCrossRefGoogle Scholar
  51. 51.
    Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159. PubMedCrossRefGoogle Scholar
  52. 52.
    Li C, Gotz J (2017) Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov 16:863–883. PubMedCrossRefGoogle Scholar
  53. 53.
    LoPresti P, Szuchet S, Papasozomenos SC, Zinkowski RP, Binder LI (1995) Functional implications for the microtubule-associated protein tau: localization in oligodendrocytes. Proc Natl Acad Sci U S A 92:10369–10373PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A, Patrick C, Trejo M, Ubhi K, Rohn TT et al (2011) Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One 6:e19338. PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269PubMedCrossRefGoogle Scholar
  56. 56.
    Masliah E, Spencer B (2015) Applications of ApoB LDLR-binding domain approach for the development of CNS-penetrating peptides for Alzheimer’s disease. Methods Mol Biol 1324:331–337. PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA et al (2015) Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 21:1154–1162. PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harbor Perspect Med 2:a006338. CrossRefGoogle Scholar
  59. 59.
    Muller R, Heinrich M, Heck S, Blohm D, Richter-Landsberg C (1997) Expression of microtubule-associated proteins MAP2 and tau in cultured rat brain oligodendrocytes. Cell Tissue Res 288:239–249PubMedCrossRefGoogle Scholar
  60. 60.
    Nisbet RM, Van der Jeugd A, Leinenga G, Evans HT, Janowicz PW, Gotz J (2017) Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain 140:1220–1230. PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Olney NT, Spina S, Miller BL (2017) Frontotemporal dementia. Neurol Clin 35:339–374. PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Otvos L Jr, Feiner L, Lang E, Szendrei GI, Goedert M, Lee VM (1994) Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404. J Neurosci Res 39:669–673. PubMedCrossRefGoogle Scholar
  63. 63.
    Overk CR, Masliah E (2014) Pathogenesis of synaptic degeneration in Alzheimer’s disease and Lewy body disease. Biochem Pharmacol 88:508–516. PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Papaleo F, Lipska BK, Weinberger DR (2012) Mouse models of genetic effects on cognition: relevance to schizophrenia. Neuropharmacology 62:1204–1220. PubMedCrossRefGoogle Scholar
  65. 65.
    Park SY, Ferreira A (2005) The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration. J Neurosci 25:5365–5375. PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Patterson KR, Remmers C, Fu Y, Brooker S, Kanaan NM, Vana L, Ward S, Reyes JF, Philibert K, Glucksman MJ et al (2011) Characterization of prefibrillar Tau oligomers in vitro and in Alzheimer disease. J Biol Chem 286:23063–23076. PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Pedersen JT, Sigurdsson EM (2015) Tau immunotherapy for Alzheimer’s disease. Trends Mol Med 21:394–402. PubMedCrossRefGoogle Scholar
  68. 68.
    Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R, Vitek MP, LaFerla FM, Rohn TT, Cotman CW (2004) Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114:121–130. PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Rockenstein E, Overk CR, Ubhi K, Mante M, Patrick C, Adame A, Bisquert A, Trejo-Morales M, Spencer B, Masliah E (2015) A novel triple repeat mutant tau transgenic model that mimics aspects of pick’s disease and fronto-temporal tauopathies. PLoS One 10:e0121570. PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Rosen O, Anglister J (2009) Epitope mapping of antibody-antigen complexes by nuclear magnetic resonance spectroscopy. Methods Mol Biol 524:37–57. PubMedCrossRefGoogle Scholar
  71. 71.
    Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NC et al (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287:3842–3849. PubMedCrossRefGoogle Scholar
  72. 72.
    Schlachetzki F, Zhu C, Pardridge WM (2002) Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem 81:203–206PubMedCrossRefGoogle Scholar
  73. 73.
    Seiberlich V, Bauer NG, Schwarz L, Ffrench-Constant C, Goldbaum O, Richter-Landsberg C (2015) Downregulation of the microtubule associated protein tau impairs process outgrowth and myelin basic protein mRNA transport in oligodendrocytes. Glia 63:1621–1635. PubMedCrossRefGoogle Scholar
  74. 74.
    Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO molecular medicine 8:595–608. PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Shah U, Dickinson BL, Blumberg RS, Simister NE, Lencer WI, Walker WA (2003) Distribution of the IgG Fc receptor, FcRn, in the human fetal intestine. Pediatr Res 53:295–301. PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Shi M, Kovac A, Korff A, Cook TJ, Ginghina C, Bullock KM, Yang L, Stewart T, Zheng D, Aro P et al (2016) CNS tau efflux via exosomes is likely increased in Parkinson’s disease but not in Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc 12:1125–1131. CrossRefGoogle Scholar
  77. 77.
    Shih HH, Tu C, Cao W, Klein A, Ramsey R, Fennell BJ, Lambert M, Ni Shuilleabhain D, Autin B, Kouranova E et al (2012) An ultra-specific avian antibody to phosphorylated tau protein reveals a unique mechanism for phosphoepitope recognition. J Biol Chem 287:44425–44434. PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Sibener L, Zaganjor I, Snyder HM, Bain LJ, Egge R, Carrillo MC (2014) Alzheimer’s disease prevalence, costs, and prevention for military personnel and veterans. Alzheimer’s Dement ia 10:S105–S110. CrossRefGoogle Scholar
  79. 79.
    Simic G, Babic Leko M, Wray S, Harrington C, Delalle I, Jovanov-Milosevic N, Bazadona D, Buee L, de Silva R, Di Giovanni G et al (2016) Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules. PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Spencer B, Desplats PA, Overk CR, Valera-Martin E, Rissman RA, Wu C, Mante M, Adame A, Florio J, Rockenstein E et al (2016) Reducing endogenous alpha-synuclein mitigates the degeneration of selective neuronal populations in an Alzheimer’s disease transgenic mouse model. J Neurosci 36:7971–7984. PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Spencer B, Emadi S, Desplats P, Eleuteri S, Michael S, Kosberg K, Shen J, Rockenstein E, Patrick C, Adame A et al (2014) ESCRT-mediated uptake and degradation of brain-targeted alpha-synuclein single chain antibody attenuates neuronal degeneration in vivo. Mol Ther 22:1753–1767. PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Spencer B, Marr RA, Gindi R, Potkar R, Michael S, Adame A, Rockenstein E, Verma IM, Masliah E (2011) Peripheral delivery of a CNS targeted, metalo-protease reduces abeta toxicity in a mouse model of Alzheimer’s disease. PLoS One 6:e16575. PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Spencer B, Michael S, Shen J, Kosberg K, Rockenstein E, Patrick C, Adame A, Masliah E (2013) Lentivirus mediated delivery of neurosin promotes clearance of wild-type alpha-synuclein and reduces the pathology in an alpha-synuclein model of LBD. Mol Ther 21:31–41. PubMedCrossRefGoogle Scholar
  84. 84.
    Spencer B, Potkar R, Metcalf J, Thrin I, Adame A, Rockenstein E, Masliah E (2016) Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) reduces neurodegeneration and increases neural precursor cell proliferation in a mouse model of Alzheimer disease. J Biol Chem 291:1905–1920. PubMedCrossRefGoogle Scholar
  85. 85.
    Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 29:13578–13588PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Spencer B, Valera E, Rockenstein E, Trejo-Morales M, Adame A, Masliah E (2015) A brain-targeted, modified neurosin (kallikrein-6) reduces alpha-synuclein accumulation in a mouse model of multiple system atrophy. Mol Neurodegener 10:48. PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Spencer B, Verma I, Desplats P, Morvinski D, Rockenstein E, Adame A, Masliah E (2014) A neuroprotective brain-penetrating endopeptidase fusion protein ameliorates Alzheimer disease pathology and restores neurogenesis. J Biol Chem 289:17917–17931. PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Spencer B, Williams S, Rockenstein E, Valera E, Wei X, Mante M, Florio J, Adame A, Masliah E, Sierks M (2016) a-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease. Ann Clin Transl Neurol 3:588–606PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Spencer BJ, Verma IM (2007) Targeted delivery of proteins across the blood-brain barrier. Proc Natl Acad Sci U S A 104:7594–7599. PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 95:7737–7741PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Tacik P, Sanchez-Contreras M, Rademakers R, Dickson DW, Wszolek ZK (2016) Genetic disorders with Tau pathology: a review of the literature and report of two patients with tauopathy and positive family histories. Neurodegener Dis 16:12–21. PubMedCrossRefGoogle Scholar
  92. 92.
    Takeda N, Kishimoto Y, Yokota O (2012) Pick’s disease. Adv Exp Med Biol 724:300–316. PubMedCrossRefGoogle Scholar
  93. 93.
    Terada S, Kinjo M, Aihara M, Takei Y, Hirokawa N (2010) Kinesin-1/Hsc70-dependent mechanism of slow axonal transport and its relation to fast axonal transport. EMBO J 29:843–854. PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Terry R, Hansen L, Masliah E (1994) Structural basis of the cognitive alterations in Alzheimer disease. In: Terry R, Katzman R (eds) Alzheimer disease. Raven Press, New York City, pp 179–196Google Scholar
  95. 95.
    Theunis C, Crespo-Biel N, Gafner V, Pihlgren M, Lopez-Deber MP, Reis P, Hickman DT, Adolfsson O, Chuard N, Ndao DM et al (2013) Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau.P301L mice that model tauopathy. PLoS One 8:e72301. PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Valera E, Spencer B, Masliah E (2016) Immunotherapeutic approaches targeting amyloid-beta, alpha-Synuclein, and Tau for the treatment of neurodegenerative disorders. Neurotherapeutics 13:179–189. PubMedCrossRefGoogle Scholar
  97. 97.
    Vranken WF, Boucher W, Stevens TJ, Fogh RH, Pajon A, Llinas M, Ulrich EL, Markley JL, Ionides J, Laue ED (2005) The CCPN data model for NMR spectroscopy: development of a software pipeline. Proteins 59:687–696. PubMedCrossRefGoogle Scholar
  98. 98.
    Wang Y, Mandelkow E (2016) Tau in physiology and pathology. Nat Rev Neurosci 17:5–21. PubMedCrossRefGoogle Scholar
  99. 99.
    Winston CN, Goetzl EJ, Akers JC, Carter BS, Rockenstein EM, Galasko D, Masliah E, Rissman RA (2016) Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement (Amst) 3:63–72. CrossRefGoogle Scholar
  100. 100.
    Woerman AL, Aoyagi A, Patel S, Kazmi SA, Lobach I, Grinberg LT, McKee AC, Seeley WW, Olson SH, Prusiner SB (2016) Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc Natl Acad Sci U S A 113:E8187–E8196. PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM (2013) Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80:402–414. PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Yoshida M, Masuda A, Kuo TT, Kobayashi K, Claypool SM, Takagawa T, Kutsumi H, Azuma T, Lencer WI, Blumberg RS (2006) IgG transport across mucosal barriers by neonatal Fc receptor for IgG and mucosal immunity. Springer Semin Immunopathol 28:397–403. PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Brian Spencer
    • 1
  • Sven Brüschweiler
    • 3
  • Marco Sealey-Cardona
    • 3
  • Edward Rockenstein
    • 1
  • Anthony Adame
    • 1
  • Jazmin Florio
    • 1
  • Michael Mante
    • 1
  • Ivy Trinh
    • 1
  • Robert A. Rissman
    • 1
    • 4
  • Robert Konrat
    • 3
  • Eliezer Masliah
    • 1
    • 2
    • 5
  1. 1.Department of NeurosciencesUniversity of CaliforniaSan DiegoUSA
  2. 2.Department of PathologyUniversity of CaliforniaSan DiegoUSA
  3. 3.Department of Computational and Structural BiologyUniversity of ViennaViennaAustria
  4. 4.Veterans Affairs San Diego Healthcare SystemSan DiegoUSA
  5. 5.Molecular Neuropathology Section, Laboratory of NeurogeneticsNational Institute on Aging, National Institutes of HealthBethesdaUSA

Personalised recommendations