Cellular and Molecular Life Sciences

, Volume 70, Issue 14, pp 2603–2619 | Cite as

Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent

  • D. Ryan
  • D. Koss
  • E. Porcu
  • H. Woodcock
  • L. Robinson
  • B. Platt
  • G. RiedelEmail author
Research Article


We recently generated an advanced mouse model of Alzheimer’s disease (AD) by targeted knock-in of single-copy mutated human amyloid precursor-protein (APP) and tau genes, crossed with a non-symptomatic presenilin (PS1A246E) over-expressing mouse line. These PLB1Triple mice presented with age-dependent and AD-relevant phenotypes. Homozygous PLB1Triple mice aged 4–12 months were assessed here in a battery of spatial learning tasks: Exp.1 radial-arm water maze (spatial reference and working memory) Exp.2 open-field water maze (spatial reference memory); Exp.3 home cage observation system with spatial learning (IntelliCage); Exp.4 spontaneous object recognition (SOR; novel object and spatial object shift). A separate test with high-expression transgenic APP mice matching the design of experiment 1 was also performed. Spatial deficits in PLB1Triple mice were confirmed at 12, but not 4 months in both water maze tasks. PSAPP mice, by contrast, presented with severe yet non-progressive spatial learning deficits already at 4 months. During tests of spatial learning in SOR and IntelliCage, PLB1Triple mice neither acquired the location of the water-rewarded corner, nor recognize novel or spatially shifted objects at 4 months, indicating these protocols to be more sensitive than the water maze. Collectively and in line with AD symptomatology, PLB1Triple mice present with a graded and progressive age-dependent loss of spatial memory that can be revealed by the use of a battery of tasks. With the emergence of subtle deficits progressively increasing in severity, PLB1Triple mice may offer a more patho-physiologically relevant model of dementia than aggressive expression models.


Knock-in mouse Amyloid Tau Spatial cognition Learning Memory 



The authors acknowledge the help of Svetlana Wittnerova with experimental elements, and part-funding from KHIDI for the initial generation of the PLB1 mice. Some experimental components were supported by an award (NS-AU-098) from the Translational Medicine Research Collaboration—a consortium made up of the Universities of Aberdeen, Dundee, Edinburgh and Glasgow, the four associated NHS Health Boards (Grampian, Tayside, Lothian and Greater Glasgow and Clyde), Scottish Enterprise and Pfizer (formerly Wyeth). The CaMKII promoter was a generous gift from Dr. Mark Mayford. Knock-in of transgenes was conducted by genOway (France).


  1. 1.
    Götz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544PubMedCrossRefGoogle Scholar
  2. 2.
    Gama Sosa MJ, De Gasperi R, Elder GA (2012) Modeling human neurodegenerative diseases in transgenic systems. Hum Genet 131:535–563PubMedCrossRefGoogle Scholar
  3. 3.
    Spires-Jones T, Knafo S (2012) Spines, plasticity, and cognition in Alzheimer’s model mice. Neural Plast 2012:10. doi: 10.1155/2012/319836 (article ID 319836)CrossRefGoogle Scholar
  4. 4.
    Games D, Adams D, Alessandrini R et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373(6514):523–527PubMedCrossRefGoogle Scholar
  5. 5.
    Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, a-beta elevation, and amyloid plaques in transgenic mice. Science 274:99–102PubMedCrossRefGoogle Scholar
  6. 6.
    Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, Godaux E, Cordell B, Van Leuven F (1999) Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 274:6483–6492PubMedCrossRefGoogle Scholar
  7. 7.
    Ishihara T, Hong M, Zhang B, Nakagawa Y, Lee MK, Trojanowski JQ, Lee VM (1999) Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24(3):751–762PubMedCrossRefGoogle Scholar
  8. 8.
    Lewis J, McGowan E, Rockwood J et al (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25(4):402–405 (Erratum in: Nat Genet 26(1):127)PubMedCrossRefGoogle Scholar
  9. 9.
    Götz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293(5534):1491–1495PubMedCrossRefGoogle Scholar
  10. 10.
    Allen B, Ingram E, Takao M et al (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22(21):9340–9351PubMedGoogle Scholar
  11. 11.
    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):337–351PubMedCrossRefGoogle Scholar
  12. 12.
    Tatebayashi Y, Miyasaka T, Chui DH, Akagi T, Mishima K, Iwasaki K, Fujiwara M, Tanemura K, Murayama M, Ishiguro K, Planel E, Sato S, Hashikawa T, Takashima A (2002) Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad Sci USA 99(21):13896–13901PubMedCrossRefGoogle Scholar
  13. 13.
    Ikeda M, Shoji M, Kawarai T et al (2005) Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice. Am J Pathol 166(2):521–531PubMedCrossRefGoogle Scholar
  14. 14.
    Borchelt DR, Thinakaran G, Eckman CB et al (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17(5):1005–1013PubMedCrossRefGoogle Scholar
  15. 15.
    Dewachter I, van Dorpe J, Spittaels K, Tesseur I, Van Den Haute C, Moechars D, Van Leuven F (2000) Modeling Alzheimer’s disease in transgenic mice: effect of age and of presenilin1 on amyloid biochemistry and pathology in APP/London mice. Exp Gerontol 35(6–7):831–841PubMedCrossRefGoogle Scholar
  16. 16.
    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
  17. 17.
    Bolmont T, Clavaguera F, Meyer-Luehmann M et al (2007) Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP × Tau transgenic mice. Am J Pathol 171(6):2012–2020PubMedCrossRefGoogle Scholar
  18. 18.
    Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 24:1063–1070PubMedCrossRefGoogle Scholar
  19. 19.
    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 A-beta and synaptic dysfunction. Neuron 39:409–421PubMedCrossRefGoogle Scholar
  20. 20.
    Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, Ozmen L, Bluethmann H, Dröse S, Brandt U, Savaskan E, Czech C, Götz J, Eckert A (2009) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci USA 106(47):20057–20062PubMedGoogle Scholar
  21. 21.
    Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688PubMedCrossRefGoogle Scholar
  22. 22.
    Clinton LK, Billings LM, Green KN, Caccamo A, Ngo J, Oddo S, McGaugh JL, LaFerla FM (2007) Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice. Neurobiol Dis 28(1):76–82PubMedCrossRefGoogle Scholar
  23. 23.
    Kobayashi DT, Chen KS (2005) Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer’s disease. Genes Brain Behav 4:173–196PubMedCrossRefGoogle Scholar
  24. 24.
    Morris RGM, Moser EI, Riedel G, Martin SJ, Sandin J, Day M, O’Carroll C (2003) Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Phil Trans R Soc Lond B Biol Ser 358:773–786CrossRefGoogle Scholar
  25. 25.
    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):10129–10140PubMedCrossRefGoogle Scholar
  26. 26.
    Holcomb L, Gordon MN, McGowan E et al (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100PubMedCrossRefGoogle Scholar
  27. 27.
    Platt B, Drever B, Koss D, Stoppelkamp S, Jyoti A, Plano A, Utan A, Merrick G, Ryan D, Melis V, Wan H, Mingarelli M, Porcu E, Scrocchi L, Welch A, Riedel G (2011) Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1. PLoS ONE 6(11):e27068PubMedCrossRefGoogle Scholar
  28. 28.
    Platt B, Welch A, Riedel G (2011) FDG-PET imaging, EEG and sleep phenotypes as translational biomarkers for research in Alzheimer’s disease. Biochem Soc Trans 9(4):874–880CrossRefGoogle Scholar
  29. 29.
    Bronson SK, Plaehn EG, Kluckman KD, Hagaman JR, Maeda N, Smithies O (1996) Single-copy transgenic mice with chosen-site integration. Proc Natl Acad Sci USA 93:9067–9072PubMedCrossRefGoogle Scholar
  30. 30.
    Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17(1):181–190PubMedCrossRefGoogle Scholar
  31. 31.
    Koss DJ, Drever BD, Stoppelkamp S, Riedel G, Platt B (2013) Age-dependent changes in hippocampal synaptic transmission and plasticity in the PLB1Triple Alzheimer mouse. Cell Mol Life Sci. doi: 10.1007/s00018-013-1273-9
  32. 32.
    Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D (1999) Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet 29:177–185PubMedCrossRefGoogle Scholar
  33. 33.
    Gordon MN, King DL, Diamond DM, Jantzen PT, Boyett KV, Hope CE, Hatcher JM, DiCarlo G, Gottschall WP, Morgan D, Arendash GW (2001) Correlation between cognitive deficits and abeta deposits in transgenic APP + PS1 mice. Neurobiol Aging 22:377–385PubMedCrossRefGoogle Scholar
  34. 34.
    Arendash GW, King DL, Gordon MN, Morgan D, Hatcher JM, Hope CE, Diamond DM (2001) Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Res 891:42–53PubMedCrossRefGoogle Scholar
  35. 35.
    Todd Roach J, Volmar CH, Dwivedi S, Town T, Crescentini R, Crawford F, Tan J, Mullan M (2004) Behavioral effects of CD40-CD40L pathway disruption in aged PSAPP mice. Brain Res 1015:161–168PubMedCrossRefGoogle Scholar
  36. 36.
    Duff K, Eckman C, Zehr C, Yu X et al (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713PubMedCrossRefGoogle Scholar
  37. 37.
    Buresova O, Bures J, Oitzl MS, Zahalka A (1985) Radial maze in the water tank: an aversively motivated spatial working memory task. Physiol Behav 34:1003–1005PubMedCrossRefGoogle Scholar
  38. 38.
    Riedel G, Micheau J, Lam AG, Roloff EL, Martin SJ, Bridge H, de Hoz L, Poeschel B, McCulloch J, Morris RG (1999) Reversible neural inactivation reveals hippocampal participation in several memory processes. Nat Neurosci 2:898–905PubMedCrossRefGoogle Scholar
  39. 39.
    Deiana S, Harrington CR, Wischik CM, Riedel G (2009) Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology 202:53–65PubMedCrossRefGoogle Scholar
  40. 40.
    Galsworthy MJ, Amrein I, Kuptsov PA, Poletaeva II, Zinn P, Rau A, Vyssotski A, Lipp HP (2005) A comparison of wild-caught wood mice and bank voles in the IntelliCage: assessing exploration, daily activity patterns and place learning paradigms. Behav Brain Res 157:211–217PubMedCrossRefGoogle Scholar
  41. 41.
    Codita A, Gumucio A, Lannfelt L, Gellerfors P, Winblad B, Mohammed AH, Nilsson LN (2010) Impaired behavior of female tg-ArcSwe APP mice in the IntelliCage: a longitudinal study. Behav Brain Res 215(1):83–94PubMedCrossRefGoogle Scholar
  42. 42.
    Good MA, Hale G (2007) The “Swedish” mutation of the amyloid precursor protein (APPswe) dissociates components of object-location memory in aged Tg2576 mice. Behav Neurosci 121(6):1180–1191PubMedCrossRefGoogle Scholar
  43. 43.
    Jyoti A, Plano A, Riedel G, Platt B (2011) EEG, activity, and sleep architecture in a transgenic AβPPSWE/PSEN1A246E Alzheimer’s disease mouse. J Alzheimers Dis 22(3):873–887Google Scholar
  44. 44.
    Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG (2000) A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 408:975–979PubMedCrossRefGoogle Scholar
  45. 45.
    Stewart S, Cacucci F, Lever C (2011) Which memory task for my mouse? a systematic review of spatial memory performance in the Tg2576 Alzheimer’s mouse model. J Alzheimer’s Dis 26:105–126Google Scholar
  46. 46.
    Filali M, Lalonde R, Theriault P, Julien C, Calon F, Planel E (2012) Cognitive and non-cognitive behaviours in the triple transgenic mouse model of Alzheimer’s disease expressing mutated APP, PS1, and Mapt (3xTg-AD). Behav Brain Res 234:334–342PubMedCrossRefGoogle Scholar
  47. 47.
    Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60PubMedCrossRefGoogle Scholar
  48. 48.
    Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain Res 31(1):47–59PubMedCrossRefGoogle Scholar
  49. 49.
    Tanila H (2012) Wading pools, fading memories-place navigation in transgenic mouse models of Alzheimer’s disease. Front Aging Neurosci 4:11PubMedCrossRefGoogle Scholar
  50. 50.
    van Groen T, Kadish I, Wyss JM (2002) Old rats remember old tricks; memories of the water maze persist for 12 months. Behav Brain Res 136:247–255PubMedCrossRefGoogle Scholar
  51. 51.
    Janus C, D’Amelio S, Amitay O, Chishti MA, Strome R, Fraser P, Carlson GA, Roder JC, George-Hyslop P, Westaway D (2000) Spatial learning in transgenic mice expressing human presenilin 1 (PS1) transgenes. Neurobiol Aging 21:541–549PubMedCrossRefGoogle Scholar
  52. 52.
    Billings LM, Green KN, McGaugh JL, LaFerla FM (2007) Learning decreases A beta*56 and tau pathology and ameliorates behavioral decline in 3xTg-AD mice. J Neurosci 27(4):751–761PubMedCrossRefGoogle Scholar
  53. 53.
    EvL Roloff, Harbaran D, Micheau J, Platt B, Riedel G (2007) Dissociation of cholinergic function in spatial and procedural learning in rats. Neuroscience 146(3):875–889CrossRefGoogle Scholar
  54. 54.
    Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408:982–985PubMedCrossRefGoogle Scholar
  55. 55.
    Hale G, Good M (2005) Impaired visuospatial recognition memory but normal object novelty detection and relative familiarity judgments in adult mice expressing the APPswe Alzheimer’s disease mutation. Behav Neurosci 119:884–891PubMedCrossRefGoogle Scholar
  56. 56.
    Good MA, Hale G, Staal V (2007) Impaired “episodic-like” object memory in adult APPswe transgenic mice. Behav Neurosci 121(2):443–448PubMedCrossRefGoogle Scholar
  57. 57.
    Gulinello M, Gertner M, Mendoza G, Schoenfeld BP, Oddo S, LaFerla F, Choi CH, McBride SM, Faber DS (2009) Validation of a 2-day water maze protocol in mice. Behav Brain Res 196(2):220–227PubMedCrossRefGoogle Scholar
  58. 58.
    Bardgett ME, Davis NN, Schultheis PJ, Griffith MS (2010) Ciproxifan, an H(3) receptor antagonist, alleviates hyperactivity and cognitive deficits in the APP(Tg2576) mouse model of Alzheimer’s disease. Neurobiol Learn Mem. (epub ahead of print)Google Scholar
  59. 59.
    Yuede CM, Zimmerman SD, Dong H, Kling MJ, Bero AW, Holtzman DM, Timson BF, Csernansky JG (2009) Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol Dis 35(3):426–432PubMedCrossRefGoogle Scholar
  60. 60.
    Taglialatela G, Hogan D, Zhang WR, Dineley KT (2009) Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition. Behav Brain Res 200(1):95–99PubMedCrossRefGoogle Scholar
  61. 61.
    Scullion GA, Kendall DA, Marsden CA, Sunter D, Pardon MC (2011) Chronic treatment with the α(2)-adrenoceptor antagonist fluparoxan prevents age-related deficits in spatial working memory in APP × PS1 transgenic mice without altering β-amyloid plaque load or astrocytosis. Neuropharmacology 60:223–234PubMedCrossRefGoogle Scholar
  62. 62.
    Woo DC, Lee SH, Lee DW, Kim SY, Kim GY, Rhim HS, Choi CB, Kim HY, Lee CU, Choe BY (2010) Regional metabolic alteration of Alzheimer’s disease in mouse brain expressing mutant human APP-PS1 by 1H HR-MAS. Behav Brain Res 211(1):125–131PubMedCrossRefGoogle Scholar
  63. 63.
    Heneka MT, Ramanathan M, Jacobs AH et al (2006) Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 26:1343–1354PubMedCrossRefGoogle Scholar
  64. 64.
    Jardanhazi-Kurutz D, Kummer MP, Terwel D, Vogel K, Dyrks T, Thiele A, Heneka MT (2010) Induced LC degeneration in APP/PS1 transgenic mice accelerates early cerebral amyloidosis and cognitive deficits. Neurochem Int 57(4):375–382PubMedCrossRefGoogle Scholar
  65. 65.
    Dewachter I, Reversé D, Caluwaerts N, Ris L, Kuipéri C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, Moechars D, Mercken M, Godaux E, Van Leuven F (2002) Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein (V717I) transgenic mice. J Neurosci 22(9):3445–3453PubMedGoogle Scholar
  66. 66.
    Mori T, Rezai-Zadeh K, Koyama N, Arendash GW, Yamaguchi H, Kakuda N, Horikoshi-Sakuraba Y, Tan J, Town T (2012) Tannic acid is a natural secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. J Biol Chem 287(9):6912–6927PubMedCrossRefGoogle Scholar
  67. 67.
    Polydoro M, Acker CM, Duff K, Castillo PE, Davies P (2009) Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology. J Neurosci 29(34):10741–10749PubMedCrossRefGoogle Scholar
  68. 68.
    Boekhoorn K, Terwel D, Biemans B et al (2006) Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci 26(13):3514–3523PubMedCrossRefGoogle Scholar
  69. 69.
    Winters BD, Forwood SE, Cowell RA, Saksida LM, Bussey TJ (2004) Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: heterogeneity of function within the temporal lobe. J Neurosci 24:5901–5908PubMedCrossRefGoogle Scholar
  70. 70.
    Rudenko O, Tkach V, Berezin V, Bock E (2009) Detection of early behavioral markers of Huntington’s disease in R6/2 mice employing an automated social home cage. Behav Brain Res 203:188–199PubMedCrossRefGoogle Scholar
  71. 71.
    Onishchenko N, Tamm C, Vahter M, Hokfelt T, Johnson JA, Johnson DA, Ceccatelli S (2007) Developmental exposure to methylmercury alters learning and induces depression-like behavior in male mice. Toxicol Sci 97:428–437PubMedCrossRefGoogle Scholar
  72. 72.
    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 316:750–754PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • D. Ryan
    • 1
  • D. Koss
    • 1
  • E. Porcu
    • 1
  • H. Woodcock
    • 1
  • L. Robinson
    • 1
  • B. Platt
    • 1
  • G. Riedel
    • 1
    Email author
  1. 1.School of Medical Sciences, College of Life Sciences and Medicine, Institute of Medical SciencesUniversity of AberdeenAberdeenScotland, UK

Personalised recommendations