Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Abstract

Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer’s disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Allen NJ, Barres BA (2009) Neuroscience: glia—more than just brain glue. Nature 457(7230):675–677

  2. Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 138(2):155–175

  3. Apostolova LG, Di LJ, Duffy EL, Brook J, Elashoff D, Tseng CH, Fairbanks L, Cummings JL (2014) Risk factors for behavioral abnormalities in mild cognitive impairment and mild Alzheimer’s disease. Dement Geriatr Cogn Disord 37(5–6):315–326

  4. Arbel-Ornath M, Hudry E, Eikermann-Haerter K, Hou S, Gregory JL, Zhao L, Betensky RA, Frosch MP, Greenberg SM, Bacskai BJ (2013) Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models. Acta Neuropathol 126(3):353–364

  5. 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 891:42–53

  6. Bales KR (2012) The value and limitations of transgenic mouse models used in drug discovery for Alzheimer’s disease: an update. Expert Opin Drug Discov 7(4):281–297

  7. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377(9770):1019–1031

  8. Bas Orth C, Vlachos A, Del Turco D, Burbach GJ, Haas CA, Mundel P, Feng G, Frotscher M, Deller T (2005) Lamina-specific distribution of Synaptopodin, an actin-associated molecule essential for the spine apparatus, in identified principal cell dendrites of the mouse hippocampus. J Comp Neurol 487(3):227–239

  9. Baxter P (2012) Astrocytes: more than just glue. Dev Med Child Neurol 54(4):291

  10. Beauquis J, Vinuesa A, Pomilio C, Pavía P, Galván V, Saravia F (2014) Neuronal and glial alterations, increased anxiety, and cognitive impairment before hippocampal amyloid deposition in PDAPP mice, model of Alzheimer’s disease. Hippocampus 24(3):257–269

  11. Bernardo A, Harrison FE, McCord M, Zhao J, Bruchey A, Davies SS, Jackson Roberts L 2nd, Mathews PM Jr, Matsuoka Y, Ariga T, RK Y, Thompson R, McDonald MP (2009) Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice. Neurobiol Aging 30(11):1777–1791

  12. Bernick C, Cummings J, Raman R, Sun X, Aisen P (2012) Age and rate of cognitive decline in Alzheimer disease: implications for clinical trials. Arch Neurol 69(7):901–905

  13. Bertram L, Tanzi RE (2008) Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 9(10):768–778

  14. Bilkei-Gorzo A (2014) Genetic mouse models of brain ageing and Alzheimer’s disease. Pharmacol Ther 142(2):244–257

  15. Braidy N, Muñoz P, Palacios AG, Castellano-Gonzalez G, Inestrosa NC, Chung RS, Sachdev P, Guillemin GJ (2012) Recent rodent models for Alzheimer’s disease: clinicalimplications and basic research. J Neural Transm (Vienna) 119(2):173–195

  16. Budni J, Bellettini-Santos T, Mina F, Garcez ML, Zugno AI (2015) The involvement of BDNF, NGF and GDNF in aging and Alzheimer’s disease. Aging Dis 6(5):331–341

  17. Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM (2012) Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging 26(5):645–654

  18. Calvo-Ochoa E, Hernández-Ortega K, Ferrera P, Morimoto S, Arias C (2014) Short-term high-fat-and-fructose feeding produces insulin signaling alterations accompanied by neurite andsynaptic reduction and astroglial activation in the rat hippocampus. 34(6):1001–1008

  19. Cao D, Lu H, Lewis TL, Li L (2007) Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J Biol Chem 282(50):36275–36282

  20. Carrera I, Etcheverría I, Li Y, Fernández-Novoa L, Lombardi V, Vigo C, Palacios HH, Benberin VV, Cacabelos R, Aliev G (2013) Immunocytochemical characterization of Alzheimer disease hallmarks in APP/PS1 transgenic micetreated with a new anti-amyloid-β vaccine. Biomed Res Int 2013:709145

  21. Carter SF, Schöll M, Almkvist O, Wall A, Engler H, Långström B, Nordberg A (2012) Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53(1):37–46

  22. Caselli RJ, Reiman EM (2013) Characterizing the preclinical stages of Alzheimer’s disease and the prospect of presymptomatic intervention. J Alzheimers Dis 33(Suppl 1):S405–S416

  23. Chen H, Yang Y, Yao HH, Tang XC, Ding JH, Wang H, Hu G (2006) Protective effects of iptakalim, a novel ATP-sensitive potassium channel opener, on global cerebral ischemia-evoked insult in gerbils. Acta Pharmacol Sin 27(6):665–672

  24. Cherry JD, Olschowka JA, O’Banion MK (2015) Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation. J Neuroinflammation 12:203

  25. Cissé M, Sanchez PE, Kim DH, Ho K, Yu GQ, Mucke L (2011) Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic mice. J Neurosci 31(29):10427–10431

  26. Derecki NC, Katzmarski N, Kipnis J, Meyer-Luehmann M (2014) Microglia as a critical player in both developmental and late-life CNS pathologies. Acta Neuropathol 128(3):333–345

  27. Deutsch LH, Rovner BW (1991) Agitation and other noncognitive abnormalities in Alzheimer’s disease. Psychiatr Clin N Am 14(2):341–351

  28. Dhikav V, Anand K (2011) Potential predictors of hippocampal atrophy in Alzheimer’s disease. Drugs Aging 28(1):1–11

  29. Dhikav V, Anand KS (2012) Are vascular factors linked to the development of hippocampal atrophy in Alzheimer’s disease? J Alzheimers Dis 32:711–718

  30. Do TM, Alata W, Dodacki A, Traversy MT, Chacun H, Pradier L, Scherrmann JM, Farinotti R, Calon F, Bourasset F (2014) Altered cerebral vascular volumes and solute transport at the blood-brain barriers of two transgenic mouse models of Alzheimer’s disease. Neuropharmacology 81:311–317

  31. Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, Chan J, Fan J, Collins J, Wellington CL (2010) ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem 285(44):34144–34154

  32. Duffy AM, Hölscher C (2013) The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer’s disease. Neuroscience 228:294–300

  33. Eckman EA, Eckman CB (2005) Abeta-degrading enzymes: modulators of Alzheimer’s disease pathogenesis and targets for therapeutic intervention. Biochem Soc Trans 33(Pt 5):1101–1105

  34. El-Amouri SS, Zhu H, Yu J, Marr R, Verma IM, Kindy MS (2008) Neprilysin: an enzyme candidate to slow the progression of Alzheimer’s disease. Am J Pathol 172(5):1342–1354

  35. Elcombe EL, Lagopoulos J, Duffy SL, Lewis SJ, Norrie L, Hickie IB, Naismith SL (2015) Hippocampal volume in older adults at risk of cognitive decline: the role of sleep, vascular risk, and depression. J Alzheimers Dis 44(4):1279–1290

  36. Erickson KI, Prakash RS, Voss MW, Chaddock L, Heo S, McLaren M, Pence BD, Martin SA, Vieira VJ, Woods JA, McAuley E, Kramer AF (2010) Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci 30(15):5368–5375

  37. Ferencz B, Gerritsen L (2015) Genetics and underlying pathology of dementia. Neuropsychol Rev 25(1):113–124

  38. Filali M, Lalonde R, Rivest S (2011) Anomalies in social behaviors and exploratory activities in an APPswe/PS1 mouse model of Alzheimer’s disease. Physiol Behav 104(5):880–885

  39. Filali M, Lalonde R, Theriault P, Julien C, Calon F, Planel E (2012) Cognitive and non-cognitive behaviors in the triple transgenic mouse model of Alzheimer’s disease expressing mutated APP, PS1, and Mapt (3xTg-AD). Behav Brain Res 234(2):334–342

  40. Garcia-Alloza M, Borrelli LA, Hyman BT, Bacskai BJ (2010) Antioxidants have a rapid and long-lasting effect on neuritic abnormalities in APP:PS1 mice. Neurobiol Aging 31(12):2058–2068

  41. Gengler S, McClean PL, McCurtin R, Gault VA, Hölscher C (2012) Val(8)GLP-1 rescues synaptic plasticity and reduces dense core plaques in APP/PS1 mice. Neurobiol Aging 33(2):265–276

  42. Gil-Bea FJ, Aisa B, Schliebs R, Ramírez MJ (2007) Increase of locomotor activity underlying the behavioral disinhibition in tg2576 mice. Behav Neurosci 121(2):340–344

  43. Guo HB, Cheng YF, Wu JG, Wang CM, Wang HT, Zhang C, Qiu ZK, Xu JP (2015) Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation. Neuroscience 290:530–542

  44. Harris JA, Devidze N, Halabisky B, Lo I, Thwin MT, Yu GQ, Bredesen DE, Masliah E, Mucke L (2010) Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer’s disease are independent of caspase cleavage of the amyloid precursor protein. J Neurosci 30(1):372–381

  45. Holtzman DM, Morris JC, Goate AM (2011) Alzheimer’s disease: the challenge of the second century. Sci Transl Med 3(77):77sr1

  46. Hooijmans CR, Graven C, Dederen PJ, Tanila H, van Groen T, Kiliaan AJ (2007) Amyloid beta deposition is related to decreased glucose transporter-1 levels and hippocampal atrophy in brains of aged APP/PS1 mice. Brain Res 1181:93–103

  47. Hsiao YH, Hung HC, Chen SH, Gean PW (2014) Social interaction rescues memory deficit in an animal model of Alzheimer’s disease by increasing BDNF-dependent hippocampal neurogenesis. J Neurosci 34(49):16207–16219

  48. Huang H, Wang L, Cao M, Marshall C, Gao J, Xiao N, Hu G, Xiao M (2015) Isolation housing exacerbates Alzheimer’s disease-like pathophysiology in aged APP/PS1 mice. Int J Neuropsychopharmacol 18:pyu116

  49. Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148(6):1204–1222

  50. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4(147):147ra111

  51. Jankowsky JL, Melnikova T, Fadale DJ, Xu GM, Slunt HH, Gonzales V, Younkin LH, Younkin SG, Borchelt DR, Savonenko AV (2005) Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer’s disease. J Neurosci 25(21):5217–5224

  52. Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17(6):157–165

  53. Janus C, Flores AY, Xu G, Borchelt DR (2015) Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains. Neurobiol Aging 36(9):2519–2532

  54. Jiang T, Yu JT, Tian Y, Tan L (2013) Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 10(8):852–867

  55. Ke HC, Huang HJ, Liang KC, Hsieh-Li HM (2011) Selective improvement of cognitive function in adult and aged APP/PS1 transgenic mice by continuous non-shock treadmill exercise. Brain Res 1403:1–11

  56. Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G (2010) Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 35(4):870–880

  57. Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM (2009) Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular a beta clearance. Neuron 64(5):632–644

  58. Knafo S, Venero C, Merino-Serrais P, Fernaud-Espinosa I, Gonzalez-Soriano J, Ferrer I, Santpere G, DeFelipe J (2009) Morphological alterations to neurons of the amygdala and impaired fear conditioning in a transgenic mouse model of Alzheimer’s disease. J Pathol 219(1):41–51

  59. Kobayashi K, Hayashi M, Nakano H, Shimazaki M, Sugimori K, Koshino Y (2004) Correlation between astrocyte apoptosis and Alzheimer changes in gray matter lesions in Alzheimer’s disease. J Alzheimers Dis 6(6):623–632

  60. Kobayashi K, Hayashi M, Nakano H, Fukutani Y, Sasaki K, Shimazaki M, Koshino Y (2002) Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer’s disease. Neuropathol Appl Neurobiol 28(3):238–251

  61. Lalonde R, Kim HD, Fukuchi K (2004) Exploratory activity, anxiety, and motor coordination in bigenic APPswe + PS1/DeltaE9 mice. Neurosci Lett 369(2):156–161

  62. Langbaum JB, Fleisher AS, Chen K, Ayutyanont N, Lopera F, Quiroz YT, Caselli RJ, Tariot PN, Reiman EM (2013) Ushering in the study and treatment of preclinical Alzheimer disease. Nat Rev Neurol 9(7):371–381

  63. Lassalle JM, Halley H, Daumas S, Verret L, Francés B (2008) Effects of the genetic background on cognitive performances of TG2576 mice. Behav Brain Res 191(1):104–110

  64. Li PP, Wang WP, Liu ZH, Xu SF, Lu WW, Wang L, Wang XL (2014) Potassium 2-(1-hydroxypentyl)-benzoate promotes long-term potentiation in Aβ1-42-injected rats and APP/PS1transgenic mice. Acta Pharmacol Sin 35(7):869–878

  65. Lipsky RH, Marini AM (2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci 1122:130–143

  66. Liu HL, Zhao G, Cai K, Zhao HH, Shi LD (2011) Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation. Behav Brain Res 218(2):308–314

  67. Lo SC, Scearce-Levie K, Sheng M (2016) Characterization of social behaviors incaspase-3 deficient mice. Sci Rep 6:18335

  68. Manczak M, Reddy PH (2012) ) abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease. Hum Mol Genet 21(23):5131–5146

  69. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330(6012):1774

  70. Mei X, Ezan P, Giaume C, Koulakoff A (2010) Astroglial connexin immunoreactivity is specifically altered at β-amyloid plaques in β-amyloid precursor protein/presenilin1 mice. Neuroscience 171(1):92–105

  71. Meyer-Luehmann M, Mielke M, Spires-Jones TL, Stoothoff W, Jones P, Bacskai BJ, Hyman BT (2009) A reporter of local dendritic translocation shows plaque- related loss of neural system function in APP-transgenic mice. J Neurosci 29(40):12636–12640

  72. Mhatre SD, Tsai CA, Rubin AJ, James ML, Andreasson KI (2015) Microglial malfunction: the third rail in the development of Alzheimer’s disease. Trends Neurosci 38(10):621–636

  73. Minkeviciene R, Ihalainen J, Malm T, Matilainen O, Keksa-Goldsteine V, Goldsteins G, Iivonen H, Leguit N, Glennon J, Koistinaho J, Banerjee P, Tanila H (2008) Age-related decrease in stimulated glutamate release and vesicular glutamate transporters in APP/PS1 transgenic and wild-type mice. J Neurochem 105(3):584–594

  74. 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(6815):982–985

  75. Morishima-Kawashima M (2014) Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloidprecursor protein by γ-secretase. Front Physiol 5:463

  76. Nasrallah IM, Wolk DA (2014) Multimodality imaging of Alzheimer disease and other neurodegenerative dementias. J Nucl Med 55(12):2003–2011

  77. Nelson RL, Guo Z, Halagappa VM, Pearson M, Gray AJ, Matsuoka Y, Brown M, Martin B, Iyun T, Maudsley S, Clark RF, Mattson MP (2007) Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Exp Neurol 205(1):166–176

  78. Obregon D, Hou H, Deng J, Giunta B, Tian J, Darlington D, Shahaduzzaman M, Zhu Y, Mori T, Mattson MP, Tan J (2012) sAPP-α modulates β-secretase activity and amyloid-β generation. Nat Commun 3:777

  79. Oksman M, Iivonen H, Hogyes E, Amtul Z, Penke B, Leenders I, Broersen L, Lütjohann D, Hartmann T, Tanila H (2006) Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on beta-amyloid accumulation in APP/PS1 transgenic mice. Neurobiol Dis 23(3):563–572

  80. O’Leary TP, Brown RE (2009) Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe/PS1dE9 mouse model of Alzheimer’s disease. Behav Brain Res 201(1):120–127

  81. Osborn LM, Kamphuis W, Wadman WJ, Hol EM (2016) Astrogliosis: an integral player in the pathogenesis of Alzheimer’s Disease. Prog Neurobiol

  82. Owen JB, Di Domenico F, Sultana R, Perluigi M, Cini C, Pierce WM, Butterfield DA (2009) Proteomics-determined differences in the concanavalin-A-fractionated proteome of hippocampus and inferior parietal lobule in subjects with Alzheimer’s disease and mild cognitive impairment: implications for progression of AD. J Proteome Res 8(2):471–482

  83. Park JH, Widi GA, Gimbel DA, Harel NY, Lee DH, Strittmatter SM (2006) Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer’s transgenic mice. J Neurosci 26(51):13279–13286

  84. Peng S, Garzon DJ, Marchese M, Klein W, Ginsberg SD, Francis BM, Mount HT, Mufson EJ, Salehi A, Fahnestock M (2009) Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease. J Neurosci 29(29):9321–9329

  85. Peng S, Wuu J, Mufson EJ, Fahnestock M (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 93(6):1412–1421

  86. Peng Y, Hu Y, Xu S, Li P, Li J, Lu L, Yang H, Feng N, Wang L, Wang X (2012) L-3-n-butylphthalide reduces tau phosphorylation and improves cognitive deficits in AβPP/PS1-Alzheimer’s transgenic mice. J Alzheimers Dis 29(2):379–391

  87. Pereda-Pérez I, Popović N, Otalora BB, Popović M, Madrid JA, Rol MA, Venero C (2013) Long-term social isolation in the adulthood results in CA1 shrinkage and cognitive impairment. Neurobiol Learn Mem 106:31–39

  88. Perrin RJ, Fagan AM, Holtzman DM (2009) Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature 461(7266):916–922

  89. Pistell PJ, Zhu M, Ingram DK (2008) Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer’s disease. Neuroscience 152(3):594–600

  90. Potter R, Patterson BW, Elbert DL, Ovod V, Kasten T, Sigurdson W, Mawuenyega K, Blazey T, Goate A, Chott R, Yarasheski KE, Holtzman DM, Morris JC, Benzinger TL, Bateman RJ (2013) Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. Sci Transl Med 5(189):189ra77

  91. Qiu WQ, Folstein MF (2006) Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging 27(2):190–198

  92. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362(4):329–344

  93. Sadowski M, Pankiewicz J, Scholtzova H, Ji Y, Quartermain D, Jensen CH, Duff K, Nixon RA, Gruen RJ, Wisniewski T (2004) Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. J Neuropathol Exp Neurol 63(5):418–428

  94. Sahlholm K, Liao F, Holtzman DM, Xu J, Mach RH (2015) Sigma-2 receptor binding is decreased in female, but not male, APP/PS1 mice. Biochem Biophys Res Commun 460(2):439–445

  95. Rademakers R, Rovelet-Lecrux A (2009) Recent insights into the molecular genetics of dementia. Trends Neurosci 32(8):451–461

  96. Ramakers IH, Verhey FR, Scheltens P, Hampel H, Soininen H, Aalten P, Rikkert MO, Verbeek MM, Spiru L, Blennow K, Trojanowski JQ, Shaw LM, Visser PJ (2013) Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment. Psychol Med 43(5):911–920

  97. Rantamäki T, Kemppainen S, Autio H, Stavén S, Koivisto H, Kojima M, Antila H, Miettinen PO, Kärkkäinen E, Karpova N, Vesa L, Lindemann L, Hoener MC, Tanila H, Castrén E (2013) The impact of Bdnf gene deficiency to the memory impairment and brain pathology of APPswe/PS1dE9 mouse model of Alzheimer’s disease. PLoS One 8(7):e68722

  98. Reiserer RS, Harrison FE, Syverud DC, McDonald MP (2007) Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer’s disease. Genes Brain Behav 6(1):54–65

  99. Roberts RO, Knopman DS, Przybelski SA, Mielke MM, Kantarci K, Preboske GM, Senjem ML, Pankratz VS, Geda YE, Boeve BF, Ivnik RJ, Rocca WA, Petersen RC, Jack CR Jr (2014) Association of type 2 diabetes with brain atrophy and cognitiveimpairment. Neurology 82(13):1132–1141

  100. Samaroo HD, Opsahl AC, Schreiber J, O’Neill SM, Marconi M, Qian J, Carvajal-Gonzalez S, Tate B, Milici AJ, Bales KR, Stephenson DT (2012) High throughput object-based image analysis of β-amyloid plaques in human and transgenic mouse brain. J Neurosci Methods 204(1):179–188

  101. Schipper HM, Bennett DA, Liberman A, Bienias JL, Schneider JA, Kelly J, Arvanitakis Z (2006) Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment. Neurobiol Aging 27(2):252–261

  102. Schnabel J (2011) Amyloid: little proteins, big clues. Nature 475(7355):S12–S14

  103. Schröder J, Pantel J (2016) Neuroimaging of hippocampal atrophy in early recognition of Alzheimer’s disease—a critical appraisal after two decades of research. Psychiatry Res 247:71–78

  104. Scott L, Feng J, Kiss T, Needle E, Atchison K, Kawabe TT, Milici AJ, Hajós-Korcsok E, Riddell D, Hajós M (2012) Age-dependent disruption in hippocampal θ oscillation in amyloid-β overproducing transgenic mice. Neurobiol Aging 33(7):1481.e13–1481.e23

  105. Shukla V, Zheng YL, Mishra SK, Amin ND, Steiner J, Grant P, Kesavapany S, Pant HC (2013) A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer’s disease phenotypes in model mice. FASEB J 27(1):174–186

  106. Smale G, Nichols NR, Brady DR, Finch CE, Horton WE Jr (1995) Evidence for apoptotic cell death in Alzheimer’s disease. Exp Neurol 133(2):225–230

  107. Sood A, Warren Beach J, Webster SJ, Terry AV, Buccafusco JJ (2007) The effects of JWB1-84-1 on memory-related task performance by amyloid Abeta transgenic mice and by young and aged monkeys. Neuropharmacology 53(5):588–600

  108. Sudduth TL, Greenstein A, Wilcock DM (2013) Intracranial injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers Aβ in APP/PS1 mice along a different time course than anti-Aβ antibodies. J Neurosci 33(23):9684–9692

  109. Tanzi RE, Bertram L (2008) Alzheimer’s disease: the latest suspect. Nature 454(7205):706–708

  110. Tanzi RE, Moir RD, Wagner SL (2004) Clearance of Alzheimer’s Abeta peptide: the many roads to perdition. Neuron 43(5):605–608

  111. Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S (2008) New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res Rev 59(1):201–220

  112. Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, Axel L, Rusinek H, Nicholson C, Zlokovic BV, Frangione B, Blennow K, Ménard J, Zetterberg H, Wisniewski T, de Leon MJ (2015) Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol 11(8):457–470

  113. Trinchese F, Liu S, Battaglia F, Walter S, Mathews PM, Arancio O (2004) Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice. Ann Neurol 55(6):801–814

  114. van de Pol LA, van der Flier WM, Korf ES, Fox NC, Barkhof F, Scheltens P (2007) Baseline predictors of rates of hippocampal atrophy in mild cognitive impairment. Neurology 69(15):1491–1497

  115. van Groen T, Kiliaan AJ, Kadish I (2006) Deposition of mouse amyloid beta in human APP/PS1 double and single AD model transgenic mice. Neurobiol Dis 23(3):653–662

  116. Wang DS, Lipton RB, Katz MJ, Davies P, Buschke H, Kuslansky G, Verghese J, Younkin SG, Eckman C, Dickson DW (2005) Decreased neprilysin immunoreactivity in Alzheimer disease, but not in pathological aging. J Neuropathol Exp Neurol 64(5):378–385

  117. Wang H, He J, Zhang R, Zhu S, Wang J, Kong L, Tan Q, Li XM (2012) Sensorimotor gating and memory deficits in an APP/PS1 double transgenic mouse model of Alzheimer’s disease. Behav Brain Res 233(1):237–243

  118. Wang Q, Xu Z, Tang J, Sun J, Gao J, Wu T, Xiao M (2013) Voluntary exercise counteracts Aβ25-35-induced memory impairment in mice. Behav Brain Res 256:618–625

  119. Varamini B, Sikalidis AK, Bradford KL (2014) Resveratrol increases cerebral glycogen synthase kinase phosphorylation as well as protein levels of drebrin and transthyretin in mice: an exploratory study. Int J Food Sci Nutr 65(1):89–96

  120. Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ (2014) Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 5:88

  121. Webster SJ, Bachstetter AD, Van Eldik LJ (2013) Comprehensive behavioral characterization of an APP/PS-1 double knock-in mouse model of Alzheimer’s disease. Alzheimers Res Ther 5(3):28

  122. Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D (2004) Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation 1:24

  123. Wirths O, Erck C, Martens H, Harmeier A, Geumann C, Jawhar S, Kumar S, Multhaup G, Walter J, Ingelsson M, Degerman-Gunnarsson M, Kalimo H, Huitinga I, Lannfelt L, Bayer TA (2010) Identification of low molecular weight pyroglutamate a{beta} oligomers in Alzheimer disease: a novel tool for therapy and diagnosis. J Biol Chem 285(53):41517–41524

  124. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M (2013) Sleep drives metabolite clearance from the adult brain. Science 342(6156):373–377

  125. Xu G, Green CC, Fromholt SE, Borchelt DR (2012) Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice. Alzheimers Res Ther 4(2):12

  126. Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J, Cai Z, Wu T, Hu G, Xiao M (2015) Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol Neurodegener 10:58

  127. Xu ZQ, Zhang LQ, Wang Q, Marshall C, Xiao N, Gao JY, Wu T, Ding J, Hu G, Xiao M (2013) Aerobic exercise combined with antioxidative treatment does not counteract moderate- or mid-stage Alzheimer-like pathophysiology of APP/PS1 mice. CNS Neurosci Ther 19(10):795–803

  128. Xu ZQ, Huang H, Chen Y, Gao JY, Xu J, Marshall C, Cai ZY, Xiao M (2016) Different expression patterns of amyloid-β precursor protein secretases in human and mouse hippocampal neurons: a potential vontribution to species differences in neuronal susceptibility to amyloid-β pathogenesis. J Alzheimers Dis 51(1):179–195

  129. Yanagisawa D, Ibrahim NF, Taguchi H, Morikawa S, Hirao K, Shirai N, Sogabe T, Tooyama I (2015) Curcumin derivative with the substitution at C-4 position, but not curcumin, is effective against amyloid pathology in APP/PS1 mice. Neurobiol Aging 36(1):201–210

  130. Yasojima K, Akiyama H, McGeer EG, McGeer PL (2001) Reduced neprilysin in high plaqueareas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci Lett 297(2):97–100

  131. Yavuz BB, Ariogul S, Cankurtaran M, Oguz KK, Halil M, Dagli N, Cankurtaran ES (2007) Hippocampal atrophy correlates with the severity of cognitive decline. Int Psychogeriatr 19(4):767–777

  132. Yousefi BH, von Reutern B, Scherübl D, Manook A, Schwaiger M, Grimmer T, Henriksen G, Förster S, Drzezga A, Wester HJ (2015) FIBT versus florbetaben and PiB: a preclinical comparison study with amyloid-PET in transgenic mice. EJNMMI Res 5:20

  133. Zahs KR, Ashe KH (2010) ‘too much good news’—are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer’s disease? Trends Neurosci 33(8):381–389

  134. Zhang Y, Zou J, Yang J, Yao Z (2015) 4Aβ1-15-derived monoclonal antibody reduces more Aβ burdens and neuroinflammation than homologous vaccine in APP/PS1 mice. Curr Alzheimer Res 12(4):384–397

  135. Zhang ZY, Daniels R, Schluesener HJ (2013) Oridonin ameliorates neuropathological changes and behavioural deficits in a mouse model of cerebral amyloidosis. J Cell Mol Med 17(12):1566–1576

Download references

Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China (30971020 and 30973517) and the Natural Science Foundation of Jiangsu Educational Department (09KJA310003).

Author information

Correspondence to Ming Xiao.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huang, H., Nie, S., Cao, M. et al. Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice. AGE 38, 303–322 (2016). https://doi.org/10.1007/s11357-016-9929-7

Download citation

Keywords

  • Aged
  • Alzheimer’s disease
  • APP/PS1 mice
  • β-amyloid
  • Hippocampal atrophy
  • Noncognitive abnormalities