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01-07-2018 | Original Paper

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

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

Published in: Acta Neuropathologica | Issue 1/2018

Abstract

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.

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. https://doi.org/10.1371/journal.pone.0010810 PubMedPubMedCentralCrossRef

Ahmad ZA, Yeap SK, Ali AM, Ho WY, Alitheen NB, Hamid M (2012) scFv antibody: principles and clinical application. Clin Dev Immunol 2012:980250. https://doi.org/10.1155/2012/980250 PubMedPubMedCentralCrossRef

Alzheimer’s Association (2015) Latest facts and figures report

Andreadis A, Brown WM, Kosik KS (1992) Structure and novel exons of the human tau gene. Biochemistry 31:10626–10633PubMedCrossRef

Arendt T, Stieler JT, Holzer M (2016) Tau and tauopathies. Brain Res Bull 126:238–292. https://doi.org/10.1016/j.brainresbull.2016.08.018 PubMedCrossRef

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. https://doi.org/10.1523/JNEUROSCI.2361-07.2007 PubMedCrossRefPubMedCentral

Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672. https://doi.org/10.1038/nrn2194 PubMedCrossRef

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. https://doi.org/10.1002/bit.24795 PubMedCrossRef

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. https://doi.org/10.1111/j.1471-4159.2011.07337.x PubMedPubMedCentralCrossRef

10.

Braczynski AK, Schulz JB, Bach JP (2017) Vaccination strategies in tauopathies and synucleinopathies. J Neurochem 143:467–488. https://doi.org/10.1111/jnc.14207 PubMedCrossRef

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. https://doi.org/10.1016/j.neurobiolaging.2014.09.007 PubMedCrossRef

12.

Caillet-Boudin ML, Buee L, Sergeant N, Lefebvre B (2015) Regulation of human MAPT gene expression. Molecular Neurodegener 10:28. https://doi.org/10.1186/s13024-015-0025-8 CrossRef

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 18:7061–7074PubMedCrossRefPubMedCentral

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. https://doi.org/10.1093/brain/awu213 PubMedCrossRef

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. https://doi.org/10.1186/s13024-016-0126-z PubMedPubMedCentralCrossRef

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. https://doi.org/10.1016/j.neuroscience.2010.04.037 PubMedCrossRef

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 114:1179–1187PubMed

18.

De Strooper B, Karran E (2016) The Cellular Phase of Alzheimer’s Disease. Cell 164:603–615. https://doi.org/10.1016/j.cell.2015.12.056 PubMedCrossRef

19.

del Alonso CA, Iqbal K (2005) Tau-induced neurodegeneration: a clue to its mechanism. J Alzheimers Dis 8:223–226CrossRef

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 6:277–293PubMedCrossRef

21.

Dickson DW, Kouri N, Murray ME, Josephs KA (2011) Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau). J Mol Neurosci 45:384–389. https://doi.org/10.1007/s12031-011-9589-0 PubMedPubMedCentralCrossRef

22.

Dixit R, Ross JL, Goldman YE, Holzbaur EL (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319:1086–1089. https://doi.org/10.1126/science.1152993 PubMedPubMedCentralCrossRef

23.

Encalada SE, Goldstein LS (2014) Biophysical challenges to axonal transport: motor-cargo deficiencies and neurodegeneration. Annu Rev Biophys 43:141–169. https://doi.org/10.1146/annurev-biophys-051013-022746 PubMedCrossRef

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. https://doi.org/10.1097/NEN.0000000000000030 PubMedCrossRef

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. https://doi.org/10.1093/brain/awx328 PubMedCrossRef

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. https://doi.org/10.1073/pnas.1630428100 PubMedPubMedCentralCrossRef

27.

Gao Y, Tan L, Yu JT, Tan L (2017) Tau in Alzheimer’s disease: mechanisms and therapeutic strategies. Curr Alzheimer Res. https://doi.org/10.2174/1567205014666170417111859 PubMedCrossRef

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 9:4225–4230PubMedPubMedCentralCrossRef

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 3:519–526PubMedCrossRef

30.

Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133:665–704. https://doi.org/10.1007/s00401-017-1707-9 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1038/nrm2101 PubMedCrossRef

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. https://doi.org/10.1038/cddis.2017.279 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1038/369488a0 PubMedCrossRef

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 35:433–446PubMedCrossRef

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 282:1914–1917PubMedCrossRef

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. https://doi.org/10.1038/31508 PubMedCrossRef

37.

Ikegami S, Harada A, Hirokawa N (2000) Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett 279:129–132PubMedCrossRef

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. https://doi.org/10.1084/jem.20162125 PubMedPubMedCentralCrossRef

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 154:6246–6251PubMed

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 92:69–74PubMedPubMedCentralCrossRef

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. https://doi.org/10.1111/jnc.12821 PubMedCrossRef

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 48:128–132PubMedCrossRef

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 323:346–349PubMedCrossRef

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. https://doi.org/10.1016/j.neurobiolaging.2011.06.006 CrossRef

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. https://doi.org/10.1186/alzrt278 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1186/alzrt277 PubMedPubMedCentralCrossRef

47.

Kosik KS, Orecchio LD, Bakalis S, Neve RL (1989) Developmentally regulated expression of specific tau sequences. Neuron 2:1389–1397PubMedCrossRef

48.

Kovacs GG (2015) Invited review: neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 41:3–23. https://doi.org/10.1111/nan.12208 PubMedCrossRef

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. https://doi.org/10.1523/JNEUROSCI.2755-14.2014 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1523/JNEUROSCI.2305-16.2017 PubMedCrossRefPubMedCentral

51.

Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159. https://doi.org/10.1146/annurev.neuro.24.1.1121 PubMedCrossRef

52.

Li C, Gotz J (2017) Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov 16:863–883. https://doi.org/10.1038/nrd.2017.155 PubMedCrossRef

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 92:10369–10373PubMedPubMedCentralCrossRef

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. https://doi.org/10.1371/journal.pone.0019338 PubMedPubMedCentralCrossRef

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 287:1265–1269PubMedCrossRef

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. https://doi.org/10.1007/978-1-4939-2806-4_21 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1038/nm.3951 PubMedPubMedCentralCrossRef

58.

Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harbor Perspect Med 2:a006338. https://doi.org/10.1101/cshperspect.a006338 CrossRef

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 288:239–249PubMedCrossRef

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. https://doi.org/10.1093/brain/awx052 PubMedPubMedCentralCrossRef

61.

Olney NT, Spina S, Miller BL (2017) Frontotemporal dementia. Neurol Clin 35:339–374. https://doi.org/10.1016/j.ncl.2017.01.008 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1002/jnr.490390607 PubMedCrossRef

63.

Overk CR, Masliah E (2014) Pathogenesis of synaptic degeneration in Alzheimer’s disease and Lewy body disease. Biochem Pharmacol 88:508–516. https://doi.org/10.1016/j.bcp.2014.01.015 PubMedPubMedCentralCrossRef

64.

Papaleo F, Lipska BK, Weinberger DR (2012) Mouse models of genetic effects on cognition: relevance to schizophrenia. Neuropharmacology 62:1204–1220. https://doi.org/10.1016/j.neuropharm.2011.04.025 PubMedCrossRef

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. https://doi.org/10.1523/JNEUROSCI.1125-05.2005 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1074/jbc.M111.237974 PubMedPubMedCentralCrossRef

67.

Pedersen JT, Sigurdsson EM (2015) Tau immunotherapy for Alzheimer’s disease. Trends Mol Med 21:394–402. https://doi.org/10.1016/j.molmed.2015.03.003 PubMedCrossRef

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. https://doi.org/10.1172/JCI20640 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1371/journal.pone.0121570 PubMedPubMedCentralCrossRef

70.

Rosen O, Anglister J (2009) Epitope mapping of antibody-antigen complexes by nuclear magnetic resonance spectroscopy. Methods Mol Biol 524:37–57. https://doi.org/10.1007/978-1-59745-450-6_3 PubMedCrossRef

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. https://doi.org/10.1074/jbc.M111.277061 PubMedCrossRef

72.

Schlachetzki F, Zhu C, Pardridge WM (2002) Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem 81:203–206PubMedCrossRef

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. https://doi.org/10.1002/glia.22832 PubMedCrossRef

74.

Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO molecular medicine 8:595–608. https://doi.org/10.15252/emmm.201606210 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1203/01.PDR.0000047663.81816.E3 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1016/j.jalz.2016.04.003 CrossRef

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. https://doi.org/10.1074/jbc.M112.415935 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1016/j.jalz.2014.04.011 CrossRef

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. https://doi.org/10.3390/biom6010006 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1523/JNEUROSCI.0775-16.2016 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1038/mt.2014.129 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1371/journal.pone.0016575 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1038/mt.2012.66 PubMedCrossRef

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. https://doi.org/10.1074/jbc.M115.678185 PubMedCrossRef

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 29:13578–13588PubMedPubMedCentralCrossRef

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. https://doi.org/10.1186/s13024-015-0043-6 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1074/jbc.M114.557439 PubMedPubMedCentralCrossRef

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 3:588–606PubMedPubMedCentralCrossRef

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. https://doi.org/10.1073/pnas.0702170104 PubMedPubMedCentralCrossRef

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 95:7737–7741PubMedPubMedCentralCrossRef

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. https://doi.org/10.1159/000440840 PubMedCrossRef

92.

Takeda N, Kishimoto Y, Yokota O (2012) Pick’s disease. Adv Exp Med Biol 724:300–316. https://doi.org/10.1007/978-1-4614-0653-2_23 PubMedCrossRef

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. https://doi.org/10.1038/emboj.2009.389 PubMedPubMedCentralCrossRef

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 179–196

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. https://doi.org/10.1371/journal.pone.0072301 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1007/s13311-015-0397-z PubMedCrossRef

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. https://doi.org/10.1002/prot.20449 PubMedCrossRef

98.

Wang Y, Mandelkow E (2016) Tau in physiology and pathology. Nat Rev Neurosci 17:5–21. https://doi.org/10.1038/nrn.2015.1 PubMedCrossRef

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. https://doi.org/10.1016/j.dadm.2016.04.001 CrossRef

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. https://doi.org/10.1073/pnas.1616344113 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1016/j.neuron.2013.07.046 PubMedPubMedCentralCrossRef

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. https://doi.org/10.1007/s00281-006-0054-z PubMedCrossRef

Title: Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders
Authors: Brian Spencer
Sven Brüschweiler
Marco Sealey-Cardona
Edward Rockenstein
Anthony Adame
Jazmin Florio
Michael Mante
Ivy Trinh
Robert A. Rissman
Robert Konrat
Eliezer Masliah
Publication date: 01-07-2018
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 1/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1869-0

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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