Motor and cognitive deficits in aged tau knockout mice in two background strains

Molecular Neurodegeneration

Ashley I Bush¹  David I Finkelstein¹  Irene Volitakis¹  Qihao Zhang²  Steve Moon¹  Scott Ayton¹  Peng Lei¹ 

[1] Oxidation Biology Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia;Institute of Biomedicine, Jinan University, Guangzhou, Guangdong, China

关键词: Aging;    Knockout;    Dementia;    Alzheimer’s disease;    Parkinson’s disease;    Tau;   

Others  :  1138753
DOI  :  10.1186/1750-1326-9-29

 received in 2014-06-06, accepted in 2014-08-10,  发布年份 2014

【 摘 要 】

Background

We recently reported that Parkinsonian and dementia phenotypes emerge between 7-12 months of age in tau^-/- mice on a Bl6/129sv mixed background. These observations were partially replicated by another group using pure Bl6 background tau^-/- mice, but notably they did not observe a cognitive phenotype. A third group using Bl6 background tau^-/- mice found cognitive impairment at 20-months of age.

Results

To reconcile the observations, here we considered the genetic, dietary and environmental variables in both studies, and performed an extended set of behavioral studies on 12-month old tau^+/+, tau^+/-, and tau^-/- mice comparing Bl6/129sv to Bl6 backgrounds. We found that tau^-/- in both backgrounds exhibited reduced tyrosine hydroxylase-positive nigral neuron and impaired motor function in all assays used, which was ameliorated by oral treatment with L-DOPA, and not confounded by changes in body weight. Tau^-/- in the C57BL6/SV129 background exhibited deficits in the Y-maze cognition task, but the mice on the Bl6 background did not.

Conclusions

These results validate our previous report on the neurodegenerative phenotypes of aged tau^-/- mice, and show that genetic background may impact the extent of cognitive impairment in these mice. Therefore excessive lowering of tau should be avoided in therapeutic strategies for AD.

【 授权许可】

   
2014 Lei et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Lei P, Ayton S, Finkelstein DI, Adlard PA, Masters CL, Bush AI: Tau protein: relevance to Parkinson’s disease. Int J Biochem Cell Biol 2010, 42:1775-1778.
• [2]Ittner A, Ke YD, Eersel JV, Gladbach A, Götz J, Ittner LM: Brief update on different roles of tau in neurodegeneration. IUBMB Life 2011, 63:495-502.
• [3]Ksiezak-Reding H, Binder LI, Yen S-HC: Immunochemical and biochemical characterization of tau proteins in normal and Alzheimer’s disease brains with Alz 50 and Tau-1. J Biol Chem 1988, 263:7948-7953.
• [4]Zhukareva V, Sundarraj S, Mann D, Sjogren M, Blenow K, Clark CM, McKeel DW, Goate A, Lippa CF, Vonsattel JP, Growdon JH, Trojanowski JQ, Lee VM: Selective reduction of soluble tau proteins in sporadic and familial frontotemporal dementias: an international follow-up study. Acta Neuropathol 2003, 105:469-476.
• [5]Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BXW, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, Mclean CA, Cappai R, Duce JA, Bush AI: Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 2012, 18:291-295.
• [6]Holth JK, Bomben VC, Reed JG, Inoue T, Younkin L, Younkin SG, Pautler RG, Botas J, Noebels JL: Tau Loss Attenuates Neuronal Network Hyperexcitability in mouse and drosophila genetic models of epilepsy. J Neurosci 2013, 33:1651-1659.
• [7]Mandelkow EM, Mandelkow E: Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harbor Perspect Med 2012, 2:a006247.
• [8]Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, Sato-Yoshitake R, Takei Y, Noda T, Hirokawa N: Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 1994, 369:488-491.
• [9]Takei Y, Teng J, Harada A, Hirokawa N: Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J Cell Biol 2000, 150:989-1000.
• [10]Yuan A, Kumar A, Peterhoff CM, Duff KE, Nixon RA: Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci 2008, 28:1682-1687.
• [11]Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, Cui B, Mucke L: tau reduction prevents A{beta}-induced defects in Axonal transport. Science 2010, 330:198.
• [12]Yuan A, Kumar A, Sasaki T, Duff K, Nixon RA: Global axonal transport rates are unaltered in htau mice in vivo. J Alzheimers Dis 2013, 37:579-586.
• [13]Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP: Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci 2001, 114:1179-1187.
• [14]Sapir T, Frotscher M, Levy T, Mandelkow EM, Reiner O: Tau’s role in the developing brain: implications for intellectual disability. Hum Mol Genet 2012, 21:1681-1692.
• [15]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: Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 2010, 142:387-397.
• [16]Ahmed T, Van der Jeugd A, Blum D, Galas MC, D’Hooge R, Buee L, Balschun D: Cognition and hippocampal synaptic plasticity in mice with a homozygous tau deletion. Neurobiol Aging 2014. doi:10.1016/j.neurobiolaging.2014.05.005
• [17]Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, Sotiropoulos I, Kim E, Collingridge GL, Takashima A, Cho K: Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc Lond B Biol Sci 2014, 369:20130144.
• [18]Ikegami S, Harada A, Hirokawa N: Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett 2000, 279:129-132.
• [19]Morris M, Koyama A, Masliah E, Mucke L: Tau reduction does not prevent motor deficits in two mouse models of Parkinson’s disease. PLoS One 2011, 6:e29257.
• [20]Tucker KL, Meyer M, Barde YA: Neurotrophins are required for nerve growth during development. Nat Neurosci 2001, 4:29-37.
• [21]Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M, Kiosea NC, Nazari S, Chen PP, Nothias F, Chan P, Teng E, Frautschy SA, Cole GM: Loss of MAP function leads to Hippocampal synapse loss and deficits in the morris water maze with aging. J Neurosci 2014, 34:7124-7136.
• [22]Morris M, Hamto P, Adame A, Devidze N, Masliah E, Mucke L: Age-appropriate cognition and subtle dopamine-independent motor deficits in aged Tau knockout mice. Neurobiol Aging 2013, 34:1523-1529.
• [23]Matsuura K, Kabuto H, Makino H, Ogawa N: Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J Neurosci Methods 1997, 73:45-48.
• [24]Lieu CA, Chinta SJ, Rane A, Andersen JK: Age-related behavioral phenotype of an astrocytic monoamine oxidase-B transgenic mouse model of Parkinson’s disease. PLoS One 2013, 8:e54200.
• [25]Gantois I, Fang K, Jiang L, Babovic D, Lawrence AJ, Ferreri V, Teper Y, Jupp B, Ziebell J, Morganti-Kossmann CM, O'Brien TJ, Nally R, Schutz G, Waddington J, Egan GF, Drago J: Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior. Proc Natl Acad Sci U S A 2007, 104:4182-4187.
• [26]Clifford JJ, Drago J, Natoli AL, Wong JY, Kinsella A, Waddington JL, Vaddadi KS: Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington’s disease. Neuroscience 2002, 109:81-88.
• [27]Paumier KL, Sukoff Rizzo SJ, Berger Z, Chen Y, Gonzales C, Kaftan E, Li L, Lotarski S, Monaghan M, Shen W, Stolyar P, Vasilyev D, Zaleska M, DH W, Dunlop J: Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson’s disease. PLoS One 2013, 8:e70274.
• [28]Glajch KE, Fleming SM, Surmeier DJ, Osten P: Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson’s disease. Behav Brain Res 2012, 230:309-316.
• [29]Amende I, Kale A, McCue S, Glazier S, Morgan JP, Hampton TG: Gait dynamics in mouse models of Parkinson’s disease and Huntington’s disease. J Neuroeng Rehabil 2005, 2:20.
• [30]Hannigan JH, Riley EP: Prenatal ethanol alters gait in rats. Alcohol 1988, 5:451-454.
• [31]Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Krüger R, Federoff M, Klein C, Goate AM, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, et al.: Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009, 41:1308-1312.
• [32]Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BM, Schjeide LM, Meissner E, Zauft U, Allen NC, Liu T, Schilling M, Anderson KJ, Beecham G, Berg D, Biernacka JM, Brice A, Destefano AL, Do CB, Eriksson N, Factor SA, Farrer MJ, Foroud T, Gasser T, Hamza T, Hardy JA, Heutink P, Hill-Burns EM, Klein C, Latourelle JC, et al.: Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: the PDGene database. PLoS Genet 2012, 8:e1002548.
• [33]Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, Wang L, Zuchner S, Konidari I, Wang G, Liu T, Schilling M, Anderson KJ, Beecham G, Berg D, Biernacka JM, Brice A, Destefano AL, Do CB, Eriksson N, Factor SA, Farrer MJ, Foroud T, Gasser T, Hamza T, Hardy JA, Heutink P, Hill-Burns EM, Klein C, Latourelle JC, et al.: Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 2010, 74:97-109.
• [34]Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, Ikram MA, Ioannidis JP, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, et al.: Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 2014. doi:10.1038/ng.3043
• [35]Duka T, Duka V, Joyce JN, Sidhu A: Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson’s disease models. FASEB J 2009, 23:2820-2830.
• [36]Elbaz A, Ross OA, Ioannidis JP, Soto-Ortolaza AI, Moisan F, Aasly J, Annesi G, Bozi M, Brighina L, Chartier-Harlin MC, Destee A, Ferrarese C, Ferraris A, Gibson JM, Gispert S, Hadjigeorgiou GM, Jasinska-Myga B, Klein C, Kruger R, Lambert JC, Lohmann K, van de Loo S, Loriot MA, Lynch T, Mellick GD, Mutez E, Nilsson C, Opala G, Puschmann A, Quattrone A, et al.: Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol 2011, 69:778-792.
• [37]Emmer KL, Waxman EA, Covy JP, Giasson BI: E46K human alpha-synuclein transgenic mice develop Lewy-like and tau pathology associated with age-dependent, detrimental motor impairment. J Biol Chem 2011, 286:35104-35118.
• [38]Qureshi HY, Paudel HK: Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and alpha-synuclein mutations promote Tau protein phosphorylation at Ser262 and destabilize microtubule cytoskeleton in vitro. J Biol Chem 2011, 286:5055-5068.
• [39]Wills J, Credle J, Haggerty T, Lee JH, Oaks AW, Sidhu A: Tauopathic changes in the striatum of A53T alpha-synuclein mutant mouse model of Parkinson’s disease. PLoS One 2011, 6:e17953.
• [40]Richard IH: Anxiety disorders in Parkinson’s disease. Adv Neurol 2005, 96:42-55.
• [41]Shinto L, Quinn J, Montine T, Dodge HH, Woodward W, Baldauf-Wagner S, Waichunas D, Bumgarner L, Bourdette D, Silbert L, Kaye J: A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease. J Alzheimers Dis 2014, 38:111-120.
• [42]Hooijmans CR, Pasker-de Jong PC, de Vries RB, Ritskes-Hoitinga M: The effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer’s pathology in animal models of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis 2012, 28:191-209.
• [43]Li ZY, Hall AM, Kelinske M, Roberson ED: Seizure resistance without Parkinsonism in aged mice after Tau reduction. Neurobiol Aging 2014. doi:10.1016/j.neurobiolaging.2014.05.001
• [44]Hare D, Ayton S, Bush A, Lei P: A delicate balance: iron metabolism and diseases of the brain. Front Aging Neurosci 2013, 5:34.
• [45]Maynard CJ, Cappai R, Volitaskis I, Cherny RA, White AR, Beyreuther K, Masters CL, Bush AI, Li Q-X: Overexpression of Alzheimer’s disease amyloid-beta opposes the age-dependent elevations of brain copper and iron. J Biol Chem 2002, 277:44670-44676.
• [46]Maynard CJ, Cappai R, Volitakis I, Cherny RA, Masters CL, Li QX, Bush AI: Gender and genetic background effects on brain metal levels in APP transgenic and normal mice: implications for Alzheimer beta-amyloid pathology. J Inorg Biochem 2006, 100:952-962.
• [47]Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR, Bapineuzumab, Clinical Trial I: Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014, 370:322-333.
• [48]Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R: Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014, 370:311-321.
• [49]Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu G-Q, Mucke L: Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 2007, 316:750-754.
• [50]Leroy K, Ando K, Laporte V, Dedecker R, Suain V, Authelet M, Héraud C, Pierrot N, Yilmaz Z, Octave J-N, Brion J-P: Lack of Tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice. Am J Pathol 2012, 181:1928-1940.
• [51]O’Leary JC 3rd, Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG, Jinwal UK, Koren J 3rd, Jones JR, Kraft C, Peters M, Abisambra JF, Duff KE, Weeber EJ, Gestwicki JE, Dickey CA: Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener 2010, 5:45.
• [52]Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Gerson JE, Singh G, Estes DM, Barrett AD, Dineley KT, Jackson GR, Kayed R: Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci 2014, 34:4260-4272.
• [53]Polydoro M, de Calignon A, Suarez-Calvet M, Sanchez L, Kay KR, Nicholls SB, Roe AD, Pitstick R, Carlson GA, Gomez-Isla T, Spires-Jones TL, Hyman BT: Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer’s disease. J Neurosci 2013, 33:13300-13311.
• [54]Bi M, Ittner A, Ke YD, Götz J, Ittner LM: Tau-targeted immunization impedes progression of Neurofibrillary histopathology in aged P301L Tau transgenic mice. PLoS One 2011, 6:e26860.
• [55]DeVos SL, Goncharoff DK, Chen G, Kebodeaux CS, Yamada K, Stewart FR, Schuler DR, Maloney SE, Wozniak DF, Rigo F, Bennett CF, Cirrito JR, Holtzman DM, Miller TM: Antisense reduction of tau in adult mice protects against seizures. J Neurosci 2013, 33:12887-12897.
• [56]Dawson HN, Cantillana V, Jansen M, Wang HY, Vitek MP, Wilcock DM, Lynch JR, Laskowitz DT: Loss of tau elicits axonal degeneration in a mouse model of Alzheimer’s disease. Neuroscience 2010, 169:516-531.
• [57]Gozes I: Microtubules (tau) as an emerging therapeutic target: NAP (davunetide). Curr Pharm Des 2011, 17:3413-3417.
• [58]Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AM, Xie SX, Ballatore C, Smith AB 3rd, Lee VM, Brunden KR: The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci 2012, 32:3601-3611.
• [59]Brunden KR, Zhang B, Carroll J, Yao Y, Potuzak JS, Hogan AM, Iba M, James MJ, Xie SX, Ballatore C, Smith AB 3rd, Lee VM, Trojanowski JQ: Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci 2010, 30:13861-13866.
• [60]Guo C, Wang T, Zheng W, Shan ZY, Teng WP, Wang ZY: Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging 2013, 34:562-575.
• [61]Ayton S, Lei P, Duce JA, Wong BX, Sedjahtera A, Adlard PA, Bush AI, Finkelstein DI: Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann Neurol 2013, 73:554-559.
• [62]Devos D, Moreau C, Devedjian JC, Kluza J, Petrault M, Laloux C, Jonneaux A, Ryckewaert G, Garcon G, Rouaix N, Duhamel A, Jissendi P, Dujardin K, Auger F, Ravasi L, Hopes L, Grolez G, Firdaus W, Sablonniere B, Strubi-Vuillaume I, Zahr N, Destee A, Corvol JC, Poltl D, Leist M, Rose C, Defebvre L, Marchetti P, Cabantchik ZI, Bordet R, et al.: Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal 2014, 21:195-210.