Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult

Molecular Neurodegeneration

Joanna L Jankowsky⁴  Pritam Das³  Heather A Born¹  Shaefali P Rodgers² 

[1] Departments of Neuroscience, BCM295, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA;Present address: Department of Psychology, University of Houston, Houston, TX, USA;Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA;Departments of Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA

关键词: Tet-off;    Tetracycline-controllable;    neurodevelopment;    Amyloid-β;    APP;    Amyloid precursor protein;    Motor hyperactivity;    Transgenic mouse;    Alzheimer’s disease;   

Others  :  863809
DOI  :  10.1186/1750-1326-7-28

 received in 2012-04-22, accepted in 2012-06-06,  发布年份 2012

【 摘 要 】

Background

Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder.

Results

We show that overexpression of the Alzheimer’s-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when matched for cortical amyloid burden, animals exposed to transgenic APP as juveniles are more active in locomotor assays than animals in which APP overexpression was delayed until adulthood. In contrast to motor activity, the age of APP onset had no effect on thigmotaxis in the open field as a rough measure of anxiety, suggesting that the interaction between APP overexpression and brain development is not unilateral.

Conclusions

Our findings indicate that locomotor hyperactivity displayed by the tet-off APP transgenic mice and several other transgenic models of Alzheimer’s disease may result from overexpression of mutant APP during postnatal brain development. Our results serve as a reminder of the potential for unexpected interactions between foreign transgenes and brain development to cause long-lasting effects on neuronal function in the adult. The tet-off APP model provides an easy means of avoiding developmental confounds by allowing transgene expression to be delayed until the mice reach adulthood.

【 授权许可】

   
2012 Rodgers et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, et al.: Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 1995, 373(6514):523-527.
• [2]Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G: Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 1996, 274(5284):99-102.
• [3]Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, et al.: Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 1996, 17(5):1005-1013.
• [4]Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L: Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci U S A 1999, 96(6):3228-3233.
• [5]Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, et al.: Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 2001, 276(24):21562-21570.
• [6]Vassar R: β-Secretase, APP and Aβ in Alzheimer's disease. Subcell Biochem 2005, 38:79-103.
• [7]St George-Hyslop PH: Molecular genetics of Alzheimer's disease. Biol Psychiatry 2000, 47(3):183-199.
• [8]Espana J, Gimenez-Llort L, Valero J, Minano A, Rabano A, Rodriguez-Alvarez J, LaFerla FM, Saura CA: Intraneuronal β-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer's disease transgenic mice. Biol Psychiatry 2010, 67(6):513-521.
• [9]Bedrosian TA, Herring KL, Weil ZM, Nelson RJ: Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice. Proc Natl Acad Sci U S A 2011, 108(28):11686-11691.
• [10]Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, et al.: Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 1999, 274(10):6483-6492.
• [11]Moechars D, Lorent K, De Strooper B, Dewachter I, Van Leuven F: Expression in brain of amyloid precursor protein mutated in the α-secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice. EMBO J 1996, 15(6):1265-1274.
• [12]Kumar-Singh S, Dewachter I, Moechars D, Lubke U, De Jonghe C, Ceuterick C, Checler F, Naidu A, Cordell B, Cras P, et al.: Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation. Neurobiol Dis 2000, 7(1):9-22.
• [13]Ambree O, Touma C, Gortz N, Keyvani K, Paulus W, Palme R, Sachser N: Activity changes and marked stereotypic behavior precede Aβ pathology in TgCRND8 Alzheimer mice. Neurobiol Aging 2006, 27(7):955-964.
• [14]Alexander G, Hanna A, Serna V, Younkin L, Younkin S, Janus C: Increased aggression in males in transgenic Tg2576 mouse model of Alzheimer's disease. Behav Brain Res 2011, 216(1):77-83.
• [15]Moechars D, Gilis M, Kuiperi C, Laenen I, Van Leuven F: Aggressive behaviour in transgenic mice expressing APP is alleviated by serotonergic drugs. Neuroreport 1998, 9(16):3561-3564.
• [16]Pugh PL, Richardson JC, Bate ST, Upton N, Sunter D: Non-cognitive behaviours in an APP/PS1 transgenic model of Alzheimer's disease. Behav Brain Res 2007, 178(1):18-28.
• [17]Vloeberghs E, Van Dam D, Coen K, Staufenbiel M, De Deyn PP: Aggressive male APP23 mice modeling behavioral alterations in dementia. Behav Neurosci 2006, 120(6):1380-1383.
• [18]Sterniczuk R, Dyck RH, Laferla FM, Antle MC: Characterization of the 3xTg-AD mouse model of Alzheimer's disease: part 1. Circadian changes. Brain Res 2010, 1348:139-148.
• [19]Bardgett ME, Davis NN, Schultheis PJ, Griffith MS: Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APP Tg2576 mouse model of Alzheimer's disease. Neurobiol Learn Mem 2011, 95(1):64-72.
• [20]Rustay NR, Cronin EA, Curzon P, Markosyan S, Bitner RS, Ellis TA, Waring JF, Decker MW, Rueter LE, Browman KE: Mice expressing the Swedish APP mutation on a 129 genetic background demonstrate consistent behavioral deficits and pathological markers of Alzheimer's disease. Brain Res 2010, 1311:136-147.
• [21]Walker JM, Fowler SW, Miller DK, Sun AY, Weisman GA, Wood WG, Sun GY, Simonyi A, Schachtman TR: Spatial learning and memory impairment and increased locomotion in a transgenic amyloid precursor protein mouse model of Alzheimer's disease. Behav Brain Res 2011, 222(1):169-175.
• [22]Arendash GW, King DL, Gordon MN, Morgan D, Hatcher JM, Hope CE, Diamond DM: Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Res 2001, 891(1–2):42-53.
• [23]Dodart JC, Meziane H, Mathis C, Bales KR, Paul SM, Ungerer A: Behavioral disturbances in transgenic mice overexpressing the V717F β-amyloid precursor protein. Behav Neurosci 1999, 113(5):982-990.
• [24]Van Dam D, D'Hooge R, Staufenbiel M, Van Ginneken C, Van Meir F, De Deyn PP: Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci 2003, 17(2):388-396.
• [25]Pietropaolo S, Feldon J, Yee BK: Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease. Behav Neurosci 2008, 122(4):733-747.
• [26]Huitron-Resendiz S, Sanchez-Alavez M, Gallegos R, Berg G, Crawford E, Giacchino JL, Games D, Henriksen SJ, Criado JR: Age-independent and age-related deficits in visuospatial learning, sleep-wake states, thermoregulation and motor activity in PDAPP mice. Brain Res 2002, 928(1–2):126-137.
• [27]Vloeberghs E, Van Dam D, Engelborghs S, Nagels G, Staufenbiel M, De Deyn PP: Altered circadian locomotor activity in APP23 mice: a model for BPSD disturbances. Eur J Neurosci 2004, 20(10):2757-2766.
• [28]Wisor JP, Edgar DM, Yesavage J, Ryan HS, McCormick CM, Lapustea N, Murphy GM: Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer's disease: a role for cholinergic transmission. Neuroscience 2005, 131(2):375-385.
• [29]Campsall KD, Mazerolle CJ, De Repentingy Y, Kothary R, Wallace VA: Characterization of transgene expression and Cre recombinase activity in a panel of Thy-1 promoter-Cre transgenic mice. Developmental dynamics : an official publication of the American Association of Anatomists 2002, 224(2):135-143.
• [30]Davis JA, Naruse S, Chen H, Eckman C, Younkin S, Price DL, Borchelt DR, Sisodia SS, Wong PC: An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos. Neuron 1998, 20(3):603-609.
• [31]Qian S, Jiang P, Guan XM, Singh G, Trumbauer ME, Yu H, Chen HY, Van de Ploeg LH, Zheng H: Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1-42/43 expression. Neuron 1998, 20(3):611-617.
• [32]Sasahara M, Fries JW, Raines EW, Gown AM, Westrum LE, Frosch MP, Bonthron DT, Ross R, Collins T: PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model. Cell 1991, 64(1):217-227.
• [33]Kojima N, Wang J, Mansuy IM, Grant SG, Mayford M, Kandel ER: Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing Fyn transgene. Proc Natl Acad Sci U S A 1997, 94(9):4761-4765.
• [34]Paulson JB, Ramsden M, Forster C, Sherman MA, McGowan E, Ashe KH: Amyloid plaque and neurofibrillary tangle pathology in a regulatable mouse model of Alzheimer's disease. Am J Pathol 2008, 173(3):762-772.
• [35]Jankowsky JL, Slunt HH, Gonzales V, Savonenko AV, Wen JC, Jenkins NA, Copeland NG, Younkin LH, Lester HA, Younkin SG, et al.: Persistent amyloidosis following suppression of Aβ production in a transgenic model of Alzheimer's disease. PLoS Medicine 2005, 2(12):e355.
• [36]Bayer KU, Lohler J, Schulman H, Harbers K: Developmental expression of the CaM kinase II isoforms: ubiquitous γ- and δ-CaM kinase II are the early isoforms and most abundant in the developing nervous system. Brain Res Mol Brain Res 1999, 70(1):147-154.
• [37]Crawley JN: Behavioral phenotyping strategies for mutant mice. Neuron 2008, 57(6):809-818.
• [38]Treit D, Fundytus M: Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol Biochem Behav 1988, 31(4):959-962.
• [39]Lee H, Sawatari A: Medium spiny neurons of the neostriatal matrix exhibit specific, stereotyped changes in dendritic arborization during a critical developmental period in mice. Eur J Neurosci 2011, 34(9):1345-1354.
• [40]Young-Pearse TL, Chen AC, Chang R, Marquez C, Selkoe DJ: Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1. Neural Dev 2008, 3:15. BioMed Central Full Text
• [41]Wang P, Yang G, Mosier DR, Chang P, Zaidi T, Gong YD, Zhao NM, Dominguez B, Lee KF, Gan WB, et al.: Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-like protein 2. J Neurosci 2005, 25(5):1219-1225.
• [42]Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H: Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J Neurosci 2009, 29(35):10788-10801.
• [43]Bittner T, Fuhrmann M, Burgold S, Jung CK, Volbracht C, Steiner H, Mitteregger G, Kretzschmar HA, Haass C, Herms J: γ-secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway. J Neurosci 2009, 29(33):10405-10409.
• [44]Hoe HS, Lee HK, Pak DT: The Upside of APP at Synapses. CNS Neurosci Ther 2010, 18(1):47-56.
• [45]Qiu WQ, Ferreira A, Miller C, Koo EH, Selkoe DJ: Cell-surface β-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J Neurosci 1995, 15(3 Pt 2):2157-2167.
• [46]Lee KJ, Moussa CE, Lee Y, Sung Y, Howell BW, Turner RS, Pak DT, Hoe HS: Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines. Neuroscience 2010, 169(1):344-356.
• [47]Mucke L, Masliah E, Johnson WB, Ruppe MD, Alford M, Rockenstein EM, Forss-Petter S, Pietropaolo M, Mallory M, Abraham CR: Synaptotrophic effects of human amyloid β protein precursors in the cortex of transgenic mice. Brain Res 1994, 666(2):151-167.
• [48]Seeger G, Gartner U, Ueberham U, Rohn S, Arendt T: FAD-mutation of APP is associated with a loss of its synaptotrophic activity. Neurobiol Dis 2009, 35(2):258-263.
• [49]Torroja L, Packard M, Gorczyca M, White K, Budnik V: The Drosophila β-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction. J Neurosci 1999, 19(18):7793-7803.
• [50]Wu J, Khan GM, Nichols RA: Dopamine release in prefrontal cortex in response to β-amyloid activation of α7 * nicotinic receptors. Brain Res 2007, 1182:82-89.
• [51]Trabace L, Kendrick KM, Castrignano S, Colaianna M, De Giorgi A, Schiavone S, Lanni C, Cuomo V, Govoni S: Soluble amyloid β1-42 reduces dopamine levels in rat prefrontal cortex: relationship to nitric oxide. Neuroscience 2007, 147(3):652-663.
• [52]Perez SE, Lazarov O, Koprich JB, Chen EY, Rodriguez-Menendez V, Lipton JW, Sisodia SS, Mufson EJ: Nigrostriatal dysfunction in familial Alzheimer's disease-linked APPswe/PS1ΔE9 transgenic mice. J Neurosci 2005, 25(44):10220-10229.
• [53]Wang A, Das P, Switzer RC, Golde TE, Jankowsky JL: Robust amyloid clearance in a mouse model of AD provides novel insights into the mechanism of Aβ immunotherapy. J Neurosci 2011, 31(11):4124-4136.
• [54]Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER: Control of memory formation through regulated expression of a CaMKII transgene. Science 1996, 274(5293):1678-1683.
• [55]Flurkey K, Currer JM (Eds): The Jackson Laboratory handbook on genetically standarized mice. 6th edition. The Jackson Laboratory, Bar Harbor, ME; 2009.
• [56]Bejar R, Yasuda R, Krugers H, Hood K, Mayford M: Transgenic calmodulin-dependent protein kinase II activation: dose-dependent effects on synaptic plasticity, learning, and memory. J Neurosci 2002, 22(13):5719-5726.
• [57]Jankowsky JL, Younkin LH, Gonzales V, Fadale DJ, Slunt HH, Lester HA, Younkin SG, Borchelt DR: Rodent Aβ modulates the solubility and distribution of amyloid deposits in transgenic mice. J Biol Chem 2007, 282(31):22707-22720.
• [58]Levites Y, Das P, Price RW, Rochette MJ, Kostura LA, McGowan EM, Murphy MP, Golde TE: Anti-Abeta42- and anti-Abeta40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J Clin Invest 2006, 116(1):193-201.
• [59]Levites Y, Smithson LA, Price RW, Dakin RS, Yuan B, Sierks MR, Kim J, McGowan E, Reed DK, Rosenberry TL, et al.: Insights into the mechanisms of action of anti-Aβ antibodies in Alzheimer's disease mouse models. FASEB J 2006, 20(14):2576-2578.
• [60]Franklin KBJ, Paxinos G: The mouse brain in stereotaxic coordinates. 3rd edition. Acadmic Press, San Diego, CA; 2008.