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

Amyloid and tau pathology of familial Alzheimer’s disease APP/PS1 mouse model in a senescence phenotype background (SAMP8)

  • 752 Accesses

  • 15 Citations

Abstract

The amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of Alzheimer’s disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern at early ages, whereas senescence-accelerated mouse prone 8 (SAMP8) has a remarkable early senescence phenotype with pathological similarities to AD. The aim of this study was the investigation and characterization of cognitive and neuropathological AD markers in a novel mouse model that combines the characteristics of the APP/PS1 transgenic mouse model with a senescence-accelerated background of SAMP8 mice. Initially, significant differences were found regarding amyloid plaque formation and cognitive abnormalities. Bearing these facts in mind, we determined a general characterization of the main AD brain molecular markers, such as alterations in amyloid pathway, neuroinflammation, and hyperphosphorylation of tau in these mice along their lifetimes. Results from this analysis revealed that APP/PS1 in SAMP8 background mice showed alterations in the pathways studied in comparison with SAMP8 and APP/PS1, demonstrating that a senescence-accelerated background exacerbated the amyloid pathology and maintained the cognitive dysfunction present in APP/PS1 mice. Changes in tau pathology, including the activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 β (GSK3β), differs, but not in a parallel manner, with amyloid disturbances.

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
Fig. 9
Fig. 10

References

  1. Agarwal A, Saleh RA, Bedaiwy MA (2003) Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril 79:829–43

  2. Ahn K, Shelton CC, Tian Y et al (2010) Activation and intrinsic gamma-secretase activity of presenilin 1. Proc Natl Acad Sci U S A 107:21435–40. doi:10.1073/pnas.1013246107

  3. Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110. doi:10.1007/s10339-011-0430-z

  4. Aso E, Lomoio S, López-González I et al (2012) Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer’s disease. Brain Pathol 22:636–53. doi:10.1111/j.1750-3639.2011.00560.x

  5. Aubele T, Kaufman R, Montalmant F, Kritzer MF (2008) Effects of gonadectomy and hormone replacement on a spontaneous novel object recognition task in adult male rats. Horm Behav 54:244–52. doi:10.1016/j.yhbeh.2008.04.001

  6. Bahrick LE, Hernandez-Reif M, Pickens JN (1997) The effect of retrieval cues on visual preferences and memory in infancy: evidence for a four-phase attention function. J Exp Child Psychol 67:1–20. doi:10.1006/jecp.1997.2399

  7. Bancher C, Brunner C, Lassmann H et al (1989) Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477:90–99

  8. 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 17:1005–13

  9. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–59

  10. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278

  11. Braak H, Braak E (1998) Evolution of neuronal changes in the course of Alzheimer’s disease. J Neural Transm Suppl 53:127–40

  12. Butterfield DA, Poon HF (2005) The senescence-accelerated prone mouse (SAMP8): a model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer’s disease. Exp Gerontol 40:774–83. doi:10.1016/j.exger.2005.05.007

  13. Campion D, Dumanchin C, Hannequin D et al (1999) Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 65:664–70. doi:10.1086/302553

  14. Canudas AM, Gutierrez-Cuesta J, Rodríguez MI et al (2005) Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM). Mech Ageing Dev 126:1300–1304. doi:10.1016/j.mad.2005.07.008

  15. Casadesús G, Gutierrez-Cuesta J, Lee H-G et al (2012) Neuronal cell cycle re-entry markers are altered in the senescence accelerated mouse P8 (SAMP8). J Alzheimers Dis 30:573–83. doi:10.3233/JAD-2012-120112

  16. Chávez-Gutiérrez L, Tolia A, Maes E et al (2008) Glu(332) in the Nicastrin ectodomain is essential for gamma-secretase complex maturation but not for its activity. J Biol Chem 283:20096–105. doi:10.1074/jbc.M803040200

  17. Codita A, Winblad B, Mohammed AH (2006) Of mice and men: more neurobiology in dementia. Curr Opin Psychiatry 19:555–63. doi:10.1097/01.yco.0000245757.06374.6a

  18. Currais A, Prior M, Dargusch R et al (2013) Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer’s disease transgenic mice. Aging Cell. doi:10.1111/acel.12185

  19. Del Valle J, Duran-Vilaregut J, Manich G et al (2010) Early amyloid accumulation in the hippocampus of SAMP8 mice. J Alzheimers Dis 19:1303–15. doi:10.3233/JAD-2010-1321

  20. Del Valle J, Duran-Vilaregut J, Manich G et al (2011) Cerebral amyloid angiopathy, blood-brain barrier disruption and amyloid accumulation in SAMP8 mice. Neurodegener Dis 8:421–9. doi:10.1159/000324757

  21. Dewachter I, van Dorpe J, Spittaels K et al (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 35:831–841. doi:10.1016/S0531-5565(00)00149-2

  22. Díaz-Moreno M, Hortigüela R, Gonçalves A et al (2013) Aβ increases neural stem cell activity in senescence-accelerated SAMP8 mice. Neurobiol Aging 34:2623–38. doi:10.1016/j.neurobiolaging.2013.05.011

  23. Enserink M (1998) First Alzheimer’s diagnosis confirmed. Science 279:2037

  24. Feng Y, Wang X (2012) Antioxidant therapies for Alzheimer’s disease. Oxid Med Cell Longev 2012:472932. doi:10.1155/2012/472932

  25. Flood JF, Morley JE (1998) Learning and memory in the SAMP8 mouse. Neurosci Biobehav Rev 22:1–20

  26. Fukumori A, Fluhrer R, Steiner H, Haass C (2010) Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of gamma-secretase-mediated intramembrane proteolysis. J Neurosci 30:7853–62. doi:10.1523/JNEUROSCI. 1443-10.2010

  27. Games D, Adams D, Alessandrini R et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–7. doi:10.1038/373523a0

  28. Games D, Buttini M, Kobayashi D et al (2006) Mice as models: transgenic approaches and Alzheimer’s disease. J Alzheimers Dis 9:133–49

  29. Gandy S, DeKosky ST (2013) Toward the treatment and prevention of Alzheimer’s disease: rational strategies and recent progress. Annu Rev Med 64:367–83. doi:10.1146/annurev-med-092611-084441

  30. Glenner GG, Wong CW (1984) Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122:1131–5

  31. Grady CL (2001) Altered brain functional connectivity and impaired short-term memory in Alzheimer’s disease. Brain 124:739–756. doi:10.1093/brain/124.4.739

  32. Guimerà A, Gironès X, Cruz-sánchez FF (2002) Actualización sobre la patología de la enfermedad de Alzheimer. Rev Esp Patol 35:21–48

  33. Guo Q, Li H, Cole AL et al (2013) Modeling Alzheimer’s disease in mouse without mutant protein overexpression: cooperative and independent effects of Aβ and tau. PLoS One 8:e80706. doi:10.1371/journal.pone.0080706

  34. Harvey RJ (2003) The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry 74:1206–1209. doi:10.1136/jnnp.74.9.1206

  35. Iqbal K, Grundke-Iqbal I (2008) Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention. J Cell Mol Med 12:38–55. doi:10.1111/j.1582-4934.2008.00225.x

  36. Irizarry MC, Soriano F, McNamara M et al (1997) Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 17:7053–7059

  37. Itzhaki RF (1994) Possible factors in the etiology of Alzheimer’s disease. Mol Neurobiol 9:1–13. doi:10.1007/BF02816099

  38. Knappenberger KS, Tian G, Ye X et al (2004) Mechanism of gamma-secretase cleavage activation: is gamma-secretase regulated through autoinhibition involving the presenilin-1 exon 9 loop? Biochemistry 43:6208–18. doi:10.1021/bi036072v

  39. Koedam ELGE, Lauffer V, van der Vlies AE et al (2010) Early- versus late-onset Alzheimer’s disease: more than age alone. J Alzheimers Dis 19:1401–8. doi:10.3233/JAD-2010-1337

  40. Kumar VB, Franko M, Banks WA et al (2009) Increase in presenilin 1 (PS1) levels in senescence-accelerated mice (SAMP8) may indirectly impair memory by affecting amyloid precursor protein (APP) processing. J Exp Biol 212:494–8. doi:10.1242/jeb.022780

  41. Li YM, Xu M, Lai MT et al (2000) Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405:689–94. doi:10.1038/35015085

  42. Lok K, Zhao H, Shen H, Lok K, Zhao H, Shen H et al (2013a) Characterization of the APP/PS1 mouse model of Alzheimer’s disease in senescence accelerated background. Neurosci Lett 557(Pt B):84–9. doi:10.1016/j.neulet.2013.10.051

  43. Lok K, Zhao H, Zhang C et al (2013b) Effects of accelerated senescence on learning and memory, locomotion and anxiety-like behavior in APP/PS1 mouse model of Alzheimer’s disease. J Neurol Sci 335:145–54. doi:10.1016/j.jns.2013.09.018

  44. Lucas JJ, Hernández F, Gómez-Ramos P et al (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20:27–39. doi:10.1093/emboj/20.1.27

  45. Manich G, Mercader C, del Valle J et al (2011) Characterization of amyloid-β granules in the hippocampus of SAMP8 mice. J Alzheimers Dis 25:535–46. doi:10.3233/JAD-2011-101713

  46. Markowska AL, Spangler EL, Ingram DK (1998) Behavioral assessment of the senescence-accelerated mouse (SAM P8 and R1). Physiol Behav 64:15–26

  47. McGowan E, Sanders S, Iwatsubo T et al (1999) Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiol Dis 6:231–44. doi:10.1006/nbdi.1999.0243

  48. Miyamoto M, Kiyota Y, Yamazaki N et al (1986) Age-related changes in learning and memory in the senescence-accelerated mouse (SAM). Physiol Behav 38:399–406

  49. Miyamoto M, Kiyota Y, Nishiyama M, Nagaoka A (1992) Senescence-accelerated mouse (SAM): age-related reduced anxiety-like behavior in the SAM-P/8 strain. Physiol Behav 51:979–85

  50. Mondragón-Rodríguez S, Perry G, Luna-Muñoz J et al (2013) Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer’s disease and Down syndrome. Neuropathol Appl Neurobiol. doi:10.1111/nan.12084

  51. Morley JE, Kumar VB, Bernardo AE et al (2000) Beta-amyloid precursor polypeptide in SAMP8 mice affects learning and memory. Peptides 21:1761–7

  52. Morley JE, Farr SA, Flood JF (2002) Antibody to amyloid beta protein alleviates impaired acquisition, retention, and memory processing in SAMP8 mice. Neurobiol Learn Mem 78:125–38. doi:10.1006/nlme.2001.4047

  53. Morley JE, Farr SA, Kumar VB, Armbrecht HJ (2012) The SAMP8 mouse: a model to develop therapeutic interventions for Alzheimer’s disease. Curr Pharm Des 18:1123–30

  54. Pallas M, Camins A, Smith MA et al (2008) From aging to Alzheimer’s disease: unveiling “the switch” with the senescence-accelerated mouse model (SAMP8). J Alzheimers Dis 15:615–24

  55. Perry G, Raina AK, Nunomura A et al (2000) How important is oxidative damage? Lessons from Alzheimer’s disease. Free Radic Biol Med 28:831–4

  56. Piedrahita D, Hernández I, López-Tobón A et al (2010) Silencing of CDK5 reduces neurofibrillary tangles in transgenic Alzheimer’s mice. J Neurosci 30:13966–76. doi:10.1523/JNEUROSCI. 3637-10.2010

  57. Pimplikar SW (2009) Reassessing the amyloid cascade hypothesis of Alzheimer’s disease. Int J Biochem Cell Biol 41:1261–8. doi:10.1016/j.biocel.2008.12.015

  58. Smith MA, Perry G, Richey PL et al (1996) Oxidative damage in Alzheimer’s. Nature 382:120–1. doi:10.1038/382120b0

  59. Swomley AM, Förster S, Keeney JT et al (2013) Abeta, oxidative stress in Alzheimer disease: evidence based on proteomics studies. Biochim Biophys Acta. doi:10.1016/j.bbadis.2013.09.015

  60. Takeda T (2009) Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice. Neurochem Res 34:639–59. doi:10.1007/s11064-009-9922-y

  61. Takeda T, Hosokawa M, Takeshita S et al (1981) A new murine model of accelerated senescence. Mech Ageing Dev 17:183–94

  62. Thinakaran G, Borchelt DR, Lee MK et al (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17:181–190

  63. Verri M, Pastoris O, Dossena M et al (2012) Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer’s disease. Int J Immunopathol Pharmacol 25:345–53

  64. Wisniewski HM, Wegiel J, Kotula L (1996) Review: David Oppenheimer Memorial Lecture 1995: some neuropathological aspects of Alzheimer’s disease and its relevance to other disciplines. Neuropathol Appl Neurobiol 22:3–11. doi:10.1111/j.1365-2990.1996.tb00839.x

  65. Wolfe MS (2013) Toward the structure of presenilin/γ-secretase and presenilin homologs. Biochim Biophys Acta 1828:2886–97. doi:10.1016/j.bbamem.2013.04.015

  66. Yagi H, Katoh S, Akiguchi I, Takeda T (1988) Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAM-P/8 as an animal model of disturbances in recent memory. Brain Res 474:86–93

  67. Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 3:219–26. doi:10.1016/S1474-4422(04)00707-0

  68. Zhu X, Lee H, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 1772:494–502. doi:10.1016/j.bbadis.2006.10.014

Download references

Acknowledgments

This study was funded by grants SAF-2012-39852, SAF2011-23631, and SAF2009-13093 from the Spanish Ministerio de Ciencia e Innovación. We thank Dr. Margaret Ellen Reynolds Adlerof for linguistic and style advice and correction of the manuscript and Ms Mar Morales and Silvia Soriano for their technical aid.

Author information

Correspondence to Mercè Pallàs.

Additional information

D. Porquet and P. Andrés-Benito contributed equally to this work.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Porquet, D., Andrés-Benito, P., Griñán-Ferré, C. et al. Amyloid and tau pathology of familial Alzheimer’s disease APP/PS1 mouse model in a senescence phenotype background (SAMP8). AGE 37, 12 (2015). https://doi.org/10.1007/s11357-015-9747-3

Download citation

Keywords

  • Familial Alzheimer’s disease (fAD)
  • Aging
  • β-Amyloid
  • Tau hyperphosphorylation
  • Cognitive impairment