Advertisement

Gene Therapy Models of Alzheimer’s Disease and Other Dementias

  • Benjamin Combs
  • Andrew Kneynsberg
  • Nicholas M. Kanaan
Part of the Methods in Molecular Biology book series (MIMB, volume 1382)

Abstract

Dementias are among the most common neurological disorders, and Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD remains a looming health crisis despite great efforts to learn the mechanisms surrounding the neuron dysfunction and neurodegeneration that accompanies AD primarily in the medial temporal lobe. In addition to AD, a group of diseases known as frontotemporal dementias (FTDs) are degenerative diseases involving atrophy and degeneration in the frontal and temporal lobe regions. Importantly, AD and a number of FTDs are collectively known as tauopathies due to the abundant accumulation of pathological tau inclusions in the brain. The precise role tau plays in disease pathogenesis remains an area of strong research focus. A critical component to effectively study any human disease is the availability of models that recapitulate key features of the disease. Accordingly, a number of animal models are currently being pursued to fill the current gaps in our knowledge of the causes of dementias and to develop effective therapeutics. Recent developments in gene therapy-based approaches, particularly in recombinant adeno-associated viruses (rAAVs), have provided new tools to study AD and other related neurodegenerative disorders. Additionally, gene therapy approaches have emerged as an intriguing possibility for treating these diseases in humans. This chapter explores the current state of rAAV models of AD and other dementias, discuss recent efforts to improve these models, and describe current and future possibilities in the use of rAAVs and other viruses in treatments of disease.

Key words

Tau protein Neurofibrillary tangle Recombinant adeno-associated virus Hippocampus Entorhinal cortex Animal model 

Notes

Acknowledgements

This work was supported by NIH/NIA grant R01AG044372 (N.M.K.).

References

  1. 1.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259PubMedCrossRefGoogle Scholar
  2. 2.
    Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82(12):4245–4249PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease [see comments]. Nature 349(6311):704–706PubMedCrossRefGoogle Scholar
  4. 4.
    Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T et al (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376(6543):775–778. doi: 10.1038/376775a0 PubMedCrossRefGoogle Scholar
  5. 5.
    Greenfield JP, Tsai J, Gouras GK, Hai B, Thinakaran G, Checler F, Sisodia SS, Greengard P, Xu H (1999) Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. Proc Natl Acad Sci U S A 96(2):742–747PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156(1):15–20PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    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(3 Pt 1):631–639PubMedCrossRefGoogle Scholar
  8. 8.
    Duering M, Grimm MO, Grimm HS, Schroder J, Hartmann T (2005) Mean age of onset in familial Alzheimer’s disease is determined by amyloid beta 42. Neurobiol Aging 26(6):785–788. doi: 10.1016/j.neurobiolaging.2004.08.002 PubMedCrossRefGoogle Scholar
  9. 9.
    Deshpande A, Mina E, Glabe C, Busciglio J (2006) Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J Neurosci 26(22):6011–6018. doi: 10.1523/JNEUROSCI.1189-06.2006 PubMedCrossRefGoogle Scholar
  10. 10.
    Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27(11):2866–2875. doi: 10.1523/JNEUROSCI.4970-06.2007 PubMedCrossRefGoogle Scholar
  11. 11.
    Marin N, Romero B, Bosch-Morell F, Llansola M, Felipo V, Roma J, Romero FJ (2000) Beta-amyloid-induced activation of caspase-3 in primary cultures of rat neurons. Mech Ageing Dev 119(1–2):63–67PubMedCrossRefGoogle Scholar
  12. 12.
    Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418(6895):291. doi: 10.1038/418291a PubMedCrossRefGoogle Scholar
  13. 13.
    Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S (2009) Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A 106(14):5907–5912. doi: 10.1073/pnas.0901229106 PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A (2002) Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A 99(9):6364–6369. doi: 10.1073/pnas.092136199, 092136199 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316(5825):750–754. doi: 10.1126/science.1141736, 316/5825/750 [pii]PubMedCrossRefGoogle Scholar
  16. 16.
    Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wolfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Gotz J (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142(3):387–397. doi: 10.1016/j.cell.2010.06.036, S0092-8674(10)00726-9 [pii]PubMedCrossRefGoogle Scholar
  17. 17.
    Drubin DG, Kirschner MW (1986) Tau protein function in living cells. J Cell Biol 103(6 Pt 2):2739–2746PubMedCrossRefGoogle Scholar
  18. 18.
    Chen J, Kanai Y, Cowan NJ, Hirokawa N (1992) Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons. Nature 360(6405):674–677. doi: 10.1038/360674a0 PubMedCrossRefGoogle Scholar
  19. 19.
    Kanaan NM, Morfini GA, LaPointe NE, Pigino GF, Patterson KR, Song Y, Andreadis A, Fu Y, Brady ST, Binder LI (2011) Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J Neurosci 31(27):9858–9868. doi: 10.1523/JNEUROSCI.0560-11.2011 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Lee G, Newman ST, Gard DL, Band H, Panchamoorthy G (1998) Tau interacts with src-family non-receptor tyrosine kinases. J Cell Sci 111(Pt 21):3167–3177PubMedGoogle Scholar
  21. 21.
    Kosik KS, Crandall JE, Mufson EJ, Neve RL (1989) Tau in situ hybridization in normal and Alzheimer brain: localization in the somatodendritic compartment. Ann Neurol 26(3):352–361. doi: 10.1002/ana.410260308 PubMedCrossRefGoogle Scholar
  22. 22.
    Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83(13):4913–4917PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261(13):6084–6089PubMedGoogle Scholar
  24. 24.
    Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293(5534):1487–1491PubMedCrossRefGoogle Scholar
  25. 25.
    Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Heutink P et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393(6686):702–705PubMedCrossRefGoogle Scholar
  26. 26.
    DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27(5):457–464. doi: 10.1002/ana.410270502 PubMedCrossRefGoogle Scholar
  27. 27.
    Kowall NW, Kosik KS (1987) Axonal disruption and aberrant localization of tau protein characterize the neuropil pathology of Alzheimer’s disease. Ann Neurol 22(5):639–643PubMedCrossRefGoogle Scholar
  28. 28.
    Bondareff W, Mountjoy CQ, Roth M, Hauser DL (1989) Neurofibrillary degeneration and neuronal loss in Alzheimer’s disease. Neurobiol Aging 10(6):709–715PubMedCrossRefGoogle Scholar
  29. 29.
    Morsch R, Simon W, Coleman PD (1999) Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 58(2):188–197PubMedCrossRefGoogle Scholar
  30. 30.
    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 U S A 111(1):510–514. doi: 10.1073/pnas.1318807111 PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Lasagna-Reeves CA, Castillo-Carranza DL, Guerrero-Muoz MJ, Jackson GR, Kayed R (2010) Preparation and characterization of neurotoxic tau oligomers. Biochemistry 49(47):10039–10041. doi: 10.1021/bi1016233 PubMedCrossRefGoogle Scholar
  32. 32.
    Tian H, Davidowitz E, Lopez P, Emadi S, Moe J, Sierks M (2013) Trimeric tau is toxic to human neuronal cells at low nanomolar concentrations. Int J Cell Biol 2013:260787. doi: 10.1155/2013/260787 PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Flach K, Hilbrich I, Schiffmann A, Gartner U, Kruger M, Leonhardt M, Waschipky H, Wick L, Arendt T, Holzer M (2012) Tau oligomers impair artificial membrane integrity and cellular viability. J Biol Chem 287(52):43223–43233. doi: 10.1074/jbc.M112.396176 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Vana L, Kanaan NM, Ugwu IC, Wuu J, Mufson EJ, Binder LI (2011) Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment and Alzheimer’s disease. Am J Pathol 179(5):2533–2550. doi: 10.1016/j.ajpath.2011.07.044 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    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 (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309(5733):476–481PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Lee VM, Trojanowski JQ (1999) Neurodegenerative tauopathies: human disease and transgenic mouse models. Neuron 24(3):507–510PubMedCrossRefGoogle Scholar
  37. 37.
    Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, McKee A, Tabaton M, Litvan I (1994) Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44(11):2015–2019PubMedCrossRefGoogle Scholar
  38. 38.
    Cervos-Navarro J, Schumacher K (1994) Neurofibrillary pathology in progressive supranuclear palsy (PSP). J Neural Transm Suppl 42:153–164PubMedCrossRefGoogle Scholar
  39. 39.
    Munoz-Garcia D, Ludwin SK (1984) Classic and generalized variants of Pick’s disease: a clinicopathological, ultrastructural, and immunocytochemical comparative study. Ann Neurol 16(4):467–480PubMedCrossRefGoogle Scholar
  40. 40.
    Rebeiz JJ, Kolodny EH, Richardson EP Jr (1968) Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18(1):20–33PubMedCrossRefGoogle Scholar
  41. 41.
    McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2012) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307, aws307 [pii]PubMedCentralPubMedGoogle Scholar
  42. 42.
    Combs B, Gamblin TC (2012) FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions. Biochemistry 51:8597–8607. doi: 10.1021/bi3010818 PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25(4):402–405PubMedCrossRefGoogle Scholar
  44. 44.
    Liu F, Gong CX (2008) Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener 3:8PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Craig LA, Hong NS, McDonald RJ (2011) Revisiting the cholinergic hypothesis in the development of Alzheimer’s disease. Neurosci Biobehav Rev 35(6):1397–1409. doi: 10.1016/j.neubiorev.2011.03.001 PubMedCrossRefGoogle Scholar
  46. 46.
    Zhao Y, Zhao B (2013) Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev 2013:316523. doi: 10.1155/2013/316523 PubMedCentralPubMedGoogle Scholar
  47. 47.
    Bamburg JR, Bloom GS (2009) Cytoskeletal pathologies of Alzheimer disease. Cell Motil Cytoskeleton 66(8):635–649. doi: 10.1002/cm.20388 PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Dolan PJ, Johnson GV (2010) The role of tau kinases in Alzheimer’s disease. Curr Opin Drug Discov Devel 13(5):595–603PubMedCentralPubMedGoogle Scholar
  49. 49.
    Takalo M, Salminen A, Soininen H, Hiltunen M, Haapasalo A (2013) Protein aggregation and degradation mechanisms in neurodegenerative diseases. Am J Neurodegener Dis 2(1):1–14PubMedCentralPubMedGoogle Scholar
  50. 50.
    Bush AI, Tanzi RE (2008) Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics 5(3):421–432. doi: 10.1016/j.nurt.2008.05.001 PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Kanaan NM, Pigino GF, Brady ST, Lazarov O, Binder LI, Morfini GA (2013) Axonal degeneration in Alzheimer’s disease: when signaling abnormalities meet the axonal transport system. Exp Neurol 246:44–53. doi: 10.1016/j.expneurol.2012.06.003 PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2(1):a006346. doi: 10.1101/cshperspect.a006346 PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Armstrong RA (2013) What causes Alzheimer’s disease? Folia Neuropathol 51(3):169–188PubMedCrossRefGoogle Scholar
  54. 54.
    Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9(7):532–544. doi: 10.1038/nrn2420, nrn2420 [pii]PubMedCrossRefGoogle Scholar
  55. 55.
    Elder GA, Gama Sosa MA, De Gasperi R (2010) Transgenic mouse models of Alzheimer’s disease. Mt Sinai J Med 77(1):69–81. doi: 10.1002/msj.20159 PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    LaFerla FM, Green KN (2012) Animal models of Alzheimer disease. Cold Spring Harb Perspect Med 2(11):a006320. doi: 10.1101/cshperspect.a006320 PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, George-Hyslop PS, Westaway D (2001) Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276(24):21562–21570. doi: 10.1074/jbc.M100710200 PubMedCrossRefGoogle Scholar
  58. 58.
    Rockenstein E, Mallory M, Mante M, Sisk A, Masliaha E (2001) Early formation of mature amyloid-beta protein deposits in a mutant APP transgenic model depends on levels of Abeta(1-42). J Neurosci Res 66(4):573–582PubMedCrossRefGoogle Scholar
  59. 59.
    Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373(6514):523–527. doi: 10.1038/373523a0 PubMedCrossRefGoogle Scholar
  60. 60.
    Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274(5284):99–102PubMedCrossRefGoogle Scholar
  61. 61.
    Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 94(24):13287–13292PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383(6602):710–713. doi: 10.1038/383710a0 PubMedCrossRefGoogle Scholar
  63. 63.
    Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O’Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, Duff K (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4(1):97–100PubMedCrossRefGoogle Scholar
  64. 64.
    Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13(2):159–170. doi: 10.1093/hmg/ddh019 PubMedCrossRefGoogle Scholar
  65. 65.
    Siman R, Reaume AG, Savage MJ, Trusko S, Lin YG, Scott RW, Flood DG (2000) Presenilin-1 P264L knock-in mutation: differential effects on abeta production, amyloid deposition, and neuronal vulnerability. J Neurosci 20(23):8717–8726PubMedGoogle Scholar
  66. 66.
    Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26(40):10129–10140. doi: 10.1523/JNEUROSCI.1202-06.2006 PubMedCrossRefGoogle Scholar
  67. 67.
    Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409–421PubMedCrossRefGoogle Scholar
  68. 68.
    Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, Rakic P, Davtyan H, Agadjanyan MG, Kepe V, Barrio JR, Bannykh S, Szekely CA, Pechnick RN, Town T (2013) A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci 33(15):6245–6256. doi: 10.1523/JNEUROSCI.3672-12.2013 PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F, Markowska AL, Borchelt DR (2005) Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 18(3):602–617. doi: 10.1016/j.nbd.2004.10.022 PubMedCrossRefGoogle Scholar
  70. 70.
    McMillan P, Korvatska E, Poorkaj P, Evstafjeva Z, Robinson L, Greenup L, Leverenz J, Schellenberg GD, D’Souza I (2008) Tau isoform regulation is region- and cell-specific in mouse brain. J Comp Neurol 511(6):788–803. doi: 10.1002/cne.21867 PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Hanes J, Zilka N, Bartkova M, Caletkova M, Dobrota D, Novak M (2009) Rat tau proteome consists of six tau isoforms: implication for animal models of human tauopathies. J Neurochem 108(5):1167–1176. doi: 10.1111/j.1471-4159.2009.05869.x PubMedCrossRefGoogle Scholar
  72. 72.
    Goedert M, Crowther RA, Spillantini MG (1998) Tau mutations cause frontotemporal dementias. Neuron 21(5):955–958PubMedCrossRefGoogle Scholar
  73. 73.
    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(3):337–351. doi: 10.1016/j.neuron.2007.01.010, S0896-6273(07)00030-X [pii]PubMedCrossRefGoogle Scholar
  74. 74.
    Tanemura K, Akagi T, Murayama M, Kikuchi N, Murayama O, Hashikawa T, Yoshiike Y, Park JM, Matsuda K, Nakao S, Sun X, Sato S, Yamaguchi H, Takashima A (2001) Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau. Neurobiol Dis 8(6):1036–1045. doi: 10.1006/nbdi.2001.0439, S0969-9961(01)90439-5 [pii]PubMedCrossRefGoogle Scholar
  75. 75.
    Gotz J, Probst A, Spillantini MG, Schafer T, Jakes R, Burki K, Goedert M (1995) Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J 14(7):1304–1313PubMedCentralPubMedGoogle Scholar
  76. 76.
    Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25(22):5446–5454. doi: 10.1523/JNEUROSCI.4637-04.2005, 25/22/5446 [pii]PubMedCrossRefGoogle Scholar
  77. 77.
    de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73(4):685–697. doi: 10.1016/j.neuron.2011.11.033, S0896-6273(12)00038-4 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    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(2), e31302. doi: 10.1371/journal.pone.0031302, PONE-D-11-23353 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Klein RL, Wang DB, King MA (2009) Versatile somatic gene transfer for modeling neurodegenerative diseases. Neurotox Res 16(3):329–342. doi: 10.1007/s12640-009-9080-7 PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Low K, Aebischer P (2012) Use of viral vectors to create animal models for Parkinson’s disease. Neurobiol Dis 48(2):189–201. doi: 10.1016/j.nbd.2011.12.038 PubMedCrossRefGoogle Scholar
  81. 81.
    Terzi D, Zachariou V (2008) Adeno-associated virus-mediated gene delivery approaches for the treatment of CNS disorders. Biotechnol J 3(12):1555–1563. doi: 10.1002/biot.200800284 PubMedCrossRefGoogle Scholar
  82. 82.
    Polinski NK, Gombash SE, Manfredsson FP, Lipton JW, Kemp CJ, Cole-Strauss A, Kanaan NM, Steece-Collier K, Kuhn NC, Wohlgenant SL, Sortwell CE (2014) Recombinant adenoassociated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. Neurobiol Aging 36:1110–1120. doi: 10.1016/j.neurobiolaging.2014.07.047 PubMedCrossRefGoogle Scholar
  83. 83.
    Klein RL, Dayton RD, Diaczynsky CG, Wang DB (2010) Pronounced microgliosis and neurodegeneration in aged rats after tau gene transfer. Neurobiol Aging 31(12):2091–2102. doi: 10.1016/j.neurobiolaging.2008.12.002 PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Wu K, Meyers CA, Guerra NK, King MA, Meyer EM (2004) The effects of rAAV2-mediated NGF gene delivery in adult and aged rats. Mol Ther 9(2):262–269. doi: 10.1016/j.ymthe.2003.11.010 PubMedCrossRefGoogle Scholar
  85. 85.
    Manfredsson FP, Burger C, Rising AC, Zuobi-Hasona K, Sullivan LF, Lewin AS, Huang J, Piercefield E, Muzyczka N, Mandel RJ (2009) Tight Long-term dynamic doxycycline responsive nigrostriatal GDNF using a single rAAV vector. Mol Ther 17(11):1857–1867. doi: 10.1038/mt.2009.196 PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Gray SJ, Foti SB, Schwartz JW, Bachaboina L, Taylor-Blake B, Coleman J, Ehlers MD, Zylka MJ, McCown TJ, Samulski RJ (2011) Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors. Hum Gene Ther 22(9):1143–1153. doi: 10.1089/hum.2010.245 PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    von Jonquieres G, Mersmann N, Klugmann CB, Harasta AE, Lutz B, Teahan O, Housley GD, Frohlich D, Kramer-Albers EM, Klugmann M (2013) Glial promoter selectivity following AAV-delivery to the immature brain. PLoS One 8(6), e65646. doi: 10.1371/journal.pone.0065646 CrossRefGoogle Scholar
  88. 88.
    Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, Yoshida H, Holzer M, Craxton M, Emson PC, Atzori C, Migheli A, Crowther RA, Ghetti B, Spillantini MG, Goedert M (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22(21):9340–9351PubMedGoogle Scholar
  89. 89.
    Aschauer DF, Kreuz S, Rumpel S (2013) Analysis of transduction efficiency, tropism and axonal transport of AAV serotypes 1, 2, 5, 6, 8 and 9 in the mouse brain. PLoS One 8(9), e76310. doi: 10.1371/journal.pone.0076310 PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Burger C, Gorbatyuk OS, Velardo MJ, Peden CS, Williams P, Zolotukhin S, Reier PJ, Mandel RJ, Muzyczka N (2004) Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol Ther 10(2):302–317. doi: 10.1016/j.ymthe.2004.05.024 PubMedCrossRefGoogle Scholar
  91. 91.
    Gao G, Sena-Esteves M (2012) Introducing genes into mammalian cells: viral vectors. In: Green MR, Sambrook J (eds) Molecular cloning: a laboratory manual, vol 2, 4. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 1209–1333Google Scholar
  92. 92.
    Tiscornia G, Singer O, Ikawa M, Verma IM (2003) A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci U S A 100(4):1844–1848. doi: 10.1073/pnas.0437912100 PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Kugler S, Kilic E, Bahr M (2003) Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene expression from an adenoviral vector in the adult rat brain depending on the transduced area. Gene Ther 10(4):337–347. doi: 10.1038/sj.gt.3301905 PubMedCrossRefGoogle Scholar
  94. 94.
    Rahim AA, Wong AM, Hoefer K, Buckley SM, Mattar CN, Cheng SH, Chan JK, Cooper JD, Waddington SN (2011) Intravenous administration of AAV2/9 to the fetal and neonatal mouse leads to differential targeting of CNS cell types and extensive transduction of the nervous system. FASEB J 25(10):3505–3518. doi: 10.1096/fj.11-182311 PubMedCrossRefGoogle Scholar
  95. 95.
    Klein RL, Lin WL, Dickson DW, Lewis J, Hutton M, Duff K, Meyer EM, King MA (2004) Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau. Am J Pathol 164(1):347–353. doi: 10.1016/S0002-9440(10)63124-0 PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Jaworski T, Dewachter I, Lechat B, Croes S, Termont A, Demedts D, Borghgraef P, Devijver H, Filipkowski RK, Kaczmarek L, Kugler S, Van Leuven F (2009) AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice. PLoS One 4(10), e7280. doi: 10.1371/journal.pone.0007280 PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Dayton RD, Wang DB, Cain CD, Schrott LM, Ramirez JJ, King MA, Klein RL (2012) Frontotemporal lobar degeneration-related proteins induce only subtle memory-related deficits when bilaterally overexpressed in the dorsal hippocampus. Exp Neurol 233(2):807–814. doi: 10.1016/j.expneurol.2011.12.002 PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Squire LR, Wixted JT, Clark RE (2007) Recognition memory and the medial temporal lobe: a new perspective. Nat Rev Neurosci 8(11):872–883. doi: 10.1038/nrn2154 PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Gomez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16(14):4491–4500PubMedGoogle Scholar
  100. 100.
    Siman R, Lin YG, Malthankar-Phatak G, Dong Y (2013) A rapid gene delivery-based mouse model for early-stage Alzheimer disease-type tauopathy. J Neuropathol Exp Neurol 72(11):1062–1071. doi: 10.1097/NEN.0000000000000006 PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Burns JM, Galvin JE, Roe CM, Morris JC, McKeel DW (2005) The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs. Neurology 64(8):1397–1403. doi: 10.1212/01.WNL.0000158423.05224.7F PubMedCrossRefGoogle Scholar
  102. 102.
    Oyanagi K, Tsuchiya K, Yamazaki M, Ikeda K (2001) Substantia nigra in progressive supranuclear palsy, corticobasal degeneration, and parkinsonism-dementia complex of Guam: specific pathological features. J Neuropathol Exp Neurol 60(4):393–402PubMedGoogle Scholar
  103. 103.
    Spillantini MG, Crowther RA, Kamphorst W, Heutink P, van Swieten JC (1998) Tau pathology in two Dutch families with mutations in the microtubule- binding region of tau. Am J Pathol 153(5):1359–1363PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol 62(4):389–397PubMedGoogle Scholar
  105. 105.
    Klein RL, Dayton RD, Lin WL, Dickson DW (2005) Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat. Neurobiol Dis 20(1):64–73. doi: 10.1016/j.nbd.2005.02.001 PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Klein RL, Dayton RD, Leidenheimer NJ, Jansen K, Golde TE, Zweig RM (2006) Efficient neuronal gene transfer with AAV8 leads to neurotoxic levels of tau or green fluorescent proteins. Mol Ther 13(3):517–527. doi: 10.1016/j.ymthe.2005.10.008 PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Klein RL, Dayton RD, Tatom JB, Diaczynsky CG, Salvatore MF (2008) Tau expression levels from various adeno-associated virus vector serotypes produce graded neurodegenerative disease states. Eur J Neurosci 27(7):1615–1625. doi: 10.1111/j.1460-9568.2008.06161.x PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Di Maria E, Tabaton M, Vigo T, Abbruzzese G, Bellone E, Donati C, Frasson E, Marchese R, Montagna P, Munoz DG, Pramstaller PP, Zanusso G, Ajmar F, Mandich P (2000) Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 47(3):374–377PubMedCrossRefGoogle Scholar
  109. 109.
    Wakabayashi K, Oyanagi K, Makifuchi T, Ikuta F, Homma A, Homma Y, Horikawa Y, Tokiguchi S (1994) Corticobasal degeneration: etiopathological significance of the cytoskeletal alterations. Acta Neuropathol 87(6):545–553PubMedCrossRefGoogle Scholar
  110. 110.
    Wang DB, Dayton RD, Zweig RM, Klein RL (2010) Transcriptome analysis of a tau overexpression model in rats implicates an early pro-inflammatory response. Exp Neurol 224(1):197–206. doi: 10.1016/j.expneurol.2010.03.011 PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Ubhi K, Rockenstein E, Doppler E, Mante M, Adame A, Patrick C, Trejo M, Crews L, Paulino A, Moessler H, Masliah E (2009) Neurofibrillary and neurodegenerative pathology in APP-transgenic mice injected with AAV2-mutant TAU: neuroprotective effects of Cerebrolysin. Acta Neuropathol 117(6):699–712. doi: 10.1007/s00401-009-0505-4 PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Howlett DR, Richardson JC, Austin A, Parsons AA, Bate ST, Davies DC, Gonzalez MI (2004) Cognitive correlates of Abeta deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes. Brain Res 1017(1-2):130–136. doi: 10.1016/j.brainres.2004.05.029 PubMedCrossRefGoogle Scholar
  113. 113.
    Richardson JC, Kendal CE, Anderson R, Priest F, Gower E, Soden P, Gray R, Topps S, Howlett DR, Lavender D, Clarke NJ, Barnes JC, Haworth R, Stewart MG, Rupniak HT (2003) Ultrastructural and behavioural changes precede amyloid deposition in a transgenic model of Alzheimer’s disease. Neuroscience 122(1):213–228PubMedCrossRefGoogle Scholar
  114. 114.
    Dassie E, Andrews MR, Bensadoun JC, Cacquevel M, Schneider BL, Aebischer P, Wouters FS, Richardson JC, Hussain I, Howlett DR, Spillantini MG, Fawcett JW (2013) Focal expression of adeno-associated viral-mutant tau induces widespread impairment in an APP mouse model. Neurobiol Aging 34(5):1355–1368. doi: 10.1016/j.neurobiolaging.2012.11.011 PubMedCrossRefGoogle Scholar
  115. 115.
    Iliev AI, Ganesan S, Bunt G, Wouters FS (2006) Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity. J Biol Chem 281(48):37195–37204. doi: 10.1074/jbc.M604863200, M604863200 [pii]PubMedCrossRefGoogle Scholar
  116. 116.
    Ramirez JJ, Poulton WE, Knelson E, Barton C, King MA, Klein RL (2011) Focal expression of mutated tau in entorhinal cortex neurons of rats impairs spatial working memory. Behav Brain Res 216(1):332–340. doi: 10.1016/j.bbr.2010.08.013 PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Jaworski T, Lechat B, Demedts D, Gielis L, Devijver H, Borghgraef P, Duimel H, Verheyen F, Kugler S, Van Leuven F (2011) Dendritic degeneration, neurovascular defects, and inflammation precede neuronal loss in a mouse model for tau-mediated neurodegeneration. Am J Pathol 179(4):2001–2015. doi: 10.1016/j.ajpath.2011.06.025 PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Lawlor PA, Bland RJ, Das P, Price RW, Holloway V, Smithson L, Dicker BL, During MJ, Young D, Golde TE (2007) Novel rat Alzheimer’s disease models based on AAV-mediated gene transfer to selectively increase hippocampal Abeta levels. Mol Neurodegener 2:11. doi: 10.1186/1750-1326-2-11 PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Vidal R, Frangione B, Rostagno A, Mead S, Revesz T, Plant G, Ghiso J (1999) A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399(6738):776–781. doi: 10.1038/21637 PubMedCrossRefGoogle Scholar
  120. 120.
    Lewis PA, Piper S, Baker M, Onstead L, Murphy MP, Hardy J, Wang R, McGowan E, Golde TE (2001) Expression of BRI-amyloid beta peptide fusion proteins: a novel method for specific high-level expression of amyloid beta peptides. Biochim Biophys Acta 1537(1):58–62PubMedCrossRefGoogle Scholar
  121. 121.
    Drummond ES, Muhling J, Martins RN, Wijaya LK, Ehlert EM, Harvey AR (2013) Pathology associated with AAV mediated expression of beta amyloid or C100 in adult mouse hippocampus and cerebellum. PLoS One 8(3), e59166. doi: 10.1371/journal.pone.0059166 PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Bolognin S, Blanchard J, Wang X, Basurto-Islas G, Tung YC, Kohlbrenner E, Grundke-Iqbal I, Iqbal K (2012) An experimental rat model of sporadic Alzheimer’s disease and rescue of cognitive impairment with a neurotrophic peptide. Acta Neuropathol 123(1):133–151. doi: 10.1007/s00401-011-0908-x PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Chu J, Giannopoulos PF, Ceballos-Diaz C, Golde TE, Pratico D (2012) Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice. Mol Neurodegener 7(1):1. doi: 10.1186/1750-1326-7-1 PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Chu J, Giannopoulos PF, Ceballos-Diaz C, Golde TE, Pratico D (2012) 5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease. Ann Neurol 72(3):442–454. doi: 10.1002/ana.23642 PubMedCentralPubMedCrossRefGoogle Scholar
  125. 125.
    Ikonomovic MD, Abrahamson EE, Uz T, Manev H, Dekosky ST (2008) Increased 5-lipoxygenase immunoreactivity in the hippocampus of patients with Alzheimer’s disease. J Histochem Cytochem 56(12):1065–1073. doi: 10.1369/jhc.2008.951855 PubMedCentralPubMedCrossRefGoogle Scholar
  126. 126.
    Mackenzie IR, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9(10):995–1007. doi: 10.1016/S1474-4422(10)70195-2 PubMedCrossRefGoogle Scholar
  127. 127.
    Tatom JB, Wang DB, Dayton RD, Skalli O, Hutton ML, Dickson DW, Klein RL (2009) Mimicking aspects of frontotemporal lobar degeneration and Lou Gehrig’s disease in rats via TDP-43 overexpression. Mol Ther 17(4):607–613. doi: 10.1038/mt.2009.3 PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Yan S, Wang CE, Wei W, Gaertig MA, Lai L, Li S, Li XJ (2014) TDP-43 causes differential pathology in neuronal versus glial cells in the mouse brain. Hum Mol Genet 23(10):2678–2693. doi: 10.1093/hmg/ddt662 PubMedCentralPubMedCrossRefGoogle Scholar
  129. 129.
    Osinde M, Clavaguera F, May-Nass R, Tolnay M, Dev KK (2008) Lentivirus Tau (P301S) expression in adult amyloid precursor protein (APP)-transgenic mice leads to tangle formation. Neuropathol Appl Neurobiol 34(5):523–531. doi: 10.1111/j.1365-2990.2008.00936.x PubMedCrossRefGoogle Scholar
  130. 130.
    Khandelwal PJ, Dumanis SB, Herman AM, Rebeck GW, Moussa CE (2012) Wild type and P301L mutant Tau promote neuro-inflammation and alpha-Synuclein accumulation in lentiviral gene delivery models. Mol Cell Neurosci 49(1):44–53. doi: 10.1016/j.mcn.2011.09.002 PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Caillierez R, Begard S, Lecolle K, Deramecourt V, Zommer N, Dujardin S, Loyens A, Dufour N, Auregan G, Winderickx J, Hantraye P, Deglon N, Buee L, Colin M (2013) Lentiviral delivery of the human wild-type tau protein mediates a slow and progressive neurodegenerative tau pathology in the rat brain. Mol Ther 21(7):1358–1368. doi: 10.1038/mt.2013.66 PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    Hebron ML, Algarzae NK, Lonskaya I, Moussa C (2014) Fractalkine signaling and Tau hyper-phosphorylation are associated with autophagic alterations in lentiviral Tau and Abeta1-42 gene transfer models. Exp Neurol 251:127–138. doi: 10.1016/j.expneurol.2013.01.009 PubMedCrossRefGoogle Scholar
  133. 133.
    Rebeck GW, Hoe HS, Moussa CE (2010) Beta-amyloid1-42 gene transfer model exhibits intraneuronal amyloid, gliosis, tau phosphorylation, and neuronal loss. J Biol Chem 285(10):7440–7446. doi: 10.1074/jbc.M109.083915 PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Herman AM, Khandelwal PJ, Rebeck GW, Moussa CE (2012) Wild type TDP-43 induces neuro-inflammation and alters APP metabolism in lentiviral gene transfer models. Exp Neurol 235(1):297–305. doi: 10.1016/j.expneurol.2012.02.011 PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Hebron M, Chen W, Miessau MJ, Lonskaya I, Moussa CE (2014) Parkin reverses TDP-43-induced cell death and failure of amino acid homeostasis. J Neurochem 129(2):350–361. doi: 10.1111/jnc.12630 PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Onorato M, Mulvihill P, Connolly J, Galloway P, Whitehouse P, Perry G (1989) Alteration of neuritic cytoarchitecture in Alzheimer disease. Prog Clin Biol Res 317:781–789PubMedGoogle Scholar
  137. 137.
    Greenamyre JT, Young AB (1989) Excitatory amino acids and Alzheimer’s disease. Neurobiol Aging 10(5):593–602PubMedCrossRefGoogle Scholar
  138. 138.
    Bassil N, Grossberg GT (2009) Novel regimens and delivery systems in the pharmacological treatment of Alzheimer’s disease. CNS Drugs 23(4):293–307PubMedCrossRefGoogle Scholar
  139. 139.
    Rafii MS, Baumann TL, Bakay RA, Ostrove JM, Siffert J, Fleisher AS, Herzog CD, Barba D, Pay M, Salmon DP, Chu Y, Kordower JH, Bishop K, Keator D, Potkin S, Bartus RT (2014) A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimer’s Dement 10:571–581. doi: 10.1016/j.jalz.2013.09.004 CrossRefGoogle Scholar
  140. 140.
    Fischer W, Wictorin K, Bjorklund A, Williams LR, Varon S, Gage FH (1987) Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329(6134):65–68. doi: 10.1038/329065a0 PubMedCrossRefGoogle Scholar
  141. 141.
    Eriksdotter Jonhagen M, Nordberg A, Amberla K, Backman L, Ebendal T, Meyerson B, Olson L, Seiger SM, Theodorsson E, Viitanen M, Winblad B, Wahlund LO (1998) Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 9(5):246–257PubMedCrossRefGoogle Scholar
  142. 142.
    Smith DE, Roberts J, Gage FH, Tuszynski MH (1999) Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. Proc Natl Acad Sci U S A 96(19):10893–10898PubMedCentralPubMedCrossRefGoogle Scholar
  143. 143.
    Mandel RJ, Gage FH, Clevenger DG, Spratt SK, Snyder RO, Leff SE (1999) Nerve growth factor expressed in the medial septum following in vivo gene delivery using a recombinant adeno-associated viral vector protects cholinergic neurons from fimbria-fornix lesion-induced degeneration. Exp Neurol 155(1):59–64. doi: 10.1006/exnr.1998.6961 PubMedCrossRefGoogle Scholar
  144. 144.
    Horowitz PM, Patterson KR, Guillozet-Bongaarts AL, Reynolds MR, Carroll CA, Weintraub ST, Bennett DA, Cryns VL, Berry RW, Binder LI (2004) Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. J Neurosci 24(36):7895–7902. doi: 10.1523/JNEUROSCI.1988-04.2004 PubMedCrossRefGoogle Scholar
  145. 145.
    Caccamo D, Katsetos CD, Herman MM, Frankfurter A, Collins VP, Rubinstein LJ (1989) Immunohistochemistry of a spontaneous murine ovarian teratoma with neuroepithelial differentiation. Neuron-associated beta-tubulin as a marker for primitive neuroepithelium. Lab Invest 60(3):390–398PubMedGoogle Scholar
  146. 146.
    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(4):826.e815–826.e830. doi: 10.1016/j.neurobiolaging.2011.06.006 CrossRefGoogle Scholar
  147. 147.
    Carmel G, Mager EM, Binder LI, Kuret J (1996) The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer’s disease pathology. J Biol Chem 271(51):32789–32795PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Benjamin Combs
    • 1
  • Andrew Kneynsberg
    • 1
    • 2
  • Nicholas M. Kanaan
    • 1
    • 2
  1. 1.Department of Translational Science and Molecular Medicine, College of Human MedicineMichigan State UniversityGrand RapidsUSA
  2. 2.Neuroscience ProgramMichigan State UniversityGrand RapidsUSA

Personalised recommendations