Neuroscience Bulletin

, Volume 34, Issue 5, pp 736–746 | Cite as

Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer’s Disease

  • Jun-Ting Yang
  • Zhao-Jun Wang
  • Hong-Yan Cai
  • Li Yuan
  • Meng-Ming Hu
  • Mei-Na WuEmail author
  • Jin-Shun QiEmail author
Original Article


Alzheimer’s disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A–cAMP response element-binding protein (PKA-CREB) and p38–mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.


Sex difference 3×Tg-AD mouse Amyloid plaque Neurofibrillary tangle Neuroinflammation Spatial memory 



We gratefully acknowledge the participants for their generous dedication to the experiment. This work was partially funded by “Sanjin Scholars” of Shanxi Province and the National Natural Science Foundation of China (31471080, 31600865, and 31700918). It was sponsored by the Fund for Shanxi Key Subjects Construction, Shanxi “1331 Project” Key Subjects Construction, and Key Laboratory of Cellular Physiology (Shanxi Medical University) in Shanxi Province.

Compliance with Ethical Standards

Conflict of interest

All authors claim that there is no conflict of interest.


  1. 1.
    Grimm MO, Mett J, Grimm HS, Hartmann T. APP function and lipids: a bidirectional link. Front Mol Neurosci 2017, 10: 63.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kim NY, Cho MH, Won SH, Kang HJ, Yoon SY, Kim DH. Sorting nexin-4 regulates beta-amyloid production by modulating beta-site-activating cleavage enzyme-1. Alzheimers Res Ther 2017, 9: 4.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Chen YC. Impact of a discordant helix on beta-amyloid structure, aggregation ability and toxicity. Eur Biophys J 2017, 46: 681–687.CrossRefPubMedGoogle Scholar
  4. 4.
    Collin L, Bohrmann B, Gopfert U, Oroszlan-Szovik K, Ozmen L, Gruninger F. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain 2014, 137: 2834–2846.CrossRefPubMedGoogle Scholar
  5. 5.
    Wilcock GK, Esiri MM. Plaques, tangles and dementia. A quantitative study. J Neurol Sci 1982, 56: 343–356.CrossRefPubMedGoogle Scholar
  6. 6.
    Leyns CEG, Holtzman DM. Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener 2017, 12: 50.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dye RV, Miller KJ, Singer EJ, Levine AJ. Hormone replacement therapy and risk for neurodegenerative diseases. Int J Alzheimers Dis 2012, 2012: 258454.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Phung TK, Waltoft BL, Laursen TM, Settnes A, Kessing LV, Mortensen PB, et al. Hysterectomy, oophorectomy and risk of dementia: a nationwide historical cohort study. Dement Geriatr Cogn Disord 2010, 30: 43–50.CrossRefPubMedGoogle Scholar
  9. 9.
    Koran MEI, Wagener M, Hohman TJ, Alzheimer’s Neuroimaging I. Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav 2017, 11: 205–213.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Koppel J, Acker C, Davies P, Lopez OL, Jimenez H, Azose M, et al. Psychotic Alzheimer’s disease is associated with gender-specific tau phosphorylation abnormalities. Neurobiol Aging 2014, 35: 2021–2028.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Carroll JC, Rosario ER, Kreimer S, Villamagna A, Gentzschein E, Stanczyk FZ, et al. Sex differences in beta-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure. Brain Res 2010, 1366: 233–245.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, et al. Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res 2008, 1216: 92–103.CrossRefPubMedGoogle Scholar
  13. 13.
    Chen YJ, Liu YL, Zhong Q, Yu YF, Su HL, Toque HA, et al. Tetrahydropalmatine protects against methamphetamine-induced spatial learning and memory impairment in mice. Neurosci Bull 2012, 28: 222–232.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yang SH, Kim J, Lee MJ, Kim Y. Abnormalities of plasma cytokines and spleen in senile APP/PS1/Tau transgenic mouse model. Sci Rep 2015, 5: 15703.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bertoni-Freddari C, Sensi SL, Giorgetti B, Balietti M, Di Stefano G, Canzoniero LM, et al. Decreased presence of perforated synapses in a triple-transgenic mouse model of Alzheimer’s disease. Rejuvenation Res 2008, 11: 309–313.CrossRefPubMedGoogle Scholar
  16. 16.
    Laws KR, Irvine K, Gale TM. Sex differences in cognitive impairment in Alzheimer’s disease. World J Psychiatry 2016, 6: 54–65.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jiao SS, Bu XL, Liu YH, Zhu C, Wang QH, Shen LL, et al. Sex dimorphism profile of Alzheimer’s disease-type pathologies in an APP/PS1 mouse model. Neurotox Res 2016, 29: 256–266.CrossRefPubMedGoogle Scholar
  18. 18.
    Clinton LK, Billings LM, Green KN, Caccamo A, Ngo J, Oddo S, et al. Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice. Neurobiol Dis 2007, 28: 76–82.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Han WN, Holscher C, Yuan L, Yang W, Wang XH, Wu MN, et al. Liraglutide protects against amyloid-beta protein-induced impairment of spatial learning and memory in rats. Neurobiol Aging 2013, 34: 576–588.CrossRefPubMedGoogle Scholar
  20. 20.
    Li B, He X, Sun Y, Li B. Developmental exposure to paraquat and maneb can impair cognition, learning and memory in Sprague-Dawley rats. Mol Biosyst 2016, 12: 3088–3097.CrossRefPubMedGoogle Scholar
  21. 21.
    Yamamoto-Sasaki M, Ozawa H, Saito T, Rosler M, Riederer P. Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type. Brain Res 1999, 824: 300–303.CrossRefPubMedGoogle Scholar
  22. 22.
    Tully T, Bourtchouladze R, Scott R, Tallman J. Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov 2003, 2: 267–277.CrossRefPubMedGoogle Scholar
  23. 23.
    Josselyn SA, Nguyen PV. CREB, synapses and memory disorders: past progress and future challenges. Curr Drug Targets CNS Neurol Disord 2005, 4: 481–497.CrossRefPubMedGoogle Scholar
  24. 24.
    Chen Y, Huang X, Zhang YW, Rockenstein E, Bu G, Golde TE, et al. Alzheimer’s beta-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of beta-amyloid. J Neurosci 2012, 32: 11390–11395.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ran I, Laplante I, Lacaille JC. CREB-dependent transcriptional control and quantal changes in persistent long-term potentiation in hippocampal interneurons. J Neurosci 2012, 32: 6335–6350.CrossRefPubMedGoogle Scholar
  26. 26.
    Yin JC, Tully T. CREB and the formation of long-term memory. Curr Opin Neurobiol 1996, 6: 264–268.CrossRefPubMedGoogle Scholar
  27. 27.
    Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 2004, 114: 1624–1634.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, Arancio O. Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J Neurosci 2005, 25: 6887–6897.CrossRefPubMedGoogle Scholar
  29. 29.
    Matsuzaki K, Yamakuni T, Hashimoto M, Haque AM, Shido O, Mimaki Y, et al. Nobiletin restoring beta-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer’s disease model rats. Neurosci Lett 2006, 400: 230–234.CrossRefPubMedGoogle Scholar
  30. 30.
    Kim SH, Nairn AC, Cairns N, Lubec G. Decreased levels of ARPP-19 and PKA in brains of Down syndrome and Alzheimer’s disease. J Neural Transm Suppl 2001: 263–272.Google Scholar
  31. 31.
    Sanchez-Mut JV, Aso E, Heyn H, Matsuda T, Bock C, Ferrer I, et al. Promoter hypermethylation of the phosphatase DUSP22 mediates PKA-dependent TAU phosphorylation and CREB activation in Alzheimer’s disease. Hippocampus 2014, 24: 363–368.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Saura CA, Valero J. The role of CREB signaling in Alzheimer’s disease and other cognitive disorders. Rev Neurosci 2011, 22: 153–169.CrossRefPubMedGoogle Scholar
  33. 33.
    Tong L, Thornton PL, Balazs R, Cotman CW. Beta-amyloid-(1-42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival Is not compromised. J Biol Chem 2001, 276: 17301–17306.CrossRefPubMedGoogle Scholar
  34. 34.
    Vitolo OV, Sant’Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M. Amyloid beta-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci U S A 2002, 99: 13217–13221.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Espana J, Valero J, Minano-Molina AJ, Masgrau R, Martin E, Guardia-Laguarta C, et al. beta-Amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1. J Neurosci 2010, 30: 9402–9410.CrossRefPubMedGoogle Scholar
  36. 36.
    Tai LM, Holloway KA, Male DK, Loughlin AJ, Romero IA. Amyloid-beta-induced occludin down-regulation and increased permeability in human brain endothelial cells is mediated by MAPK activation. J Cell Mol Med 2010, 14: 1101–1112.PubMedGoogle Scholar
  37. 37.
    Kuo YC, Tsao CW. Neuroprotection against apoptosis of SK-N-MC cells using RMP-7- and lactoferrin-grafted liposomes carrying quercetin. Int J Nanomedicine 2017, 12: 2857–2869.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wan Z, Mah D, Simtchouk S, Klegeris A, Little JP. Globular adiponectin induces a pro-inflammatory response in human astrocytic cells. Biochem Biophys Res Commun 2014, 446: 37–42.CrossRefPubMedGoogle Scholar
  39. 39.
    Ghasemi R, Zarifkar A, Rastegar K, maghsoudi N, Moosavi M. Insulin protects against Abeta-induced spatial memory impairment, hippocampal apoptosis and MAPKs signaling disruption. Neuropharmacology 2014, 85: 113–120.CrossRefPubMedGoogle Scholar
  40. 40.
    Ghasemi R, Zarifkar A, Rastegar K, Maghsoudi N, Moosavi M. Repeated intra-hippocampal injection of beta-amyloid 25-35 induces a reproducible impairment of learning and memory: considering caspase-3 and MAPKs activity. Eur J Pharmacol 2014, 726: 33–40.CrossRefPubMedGoogle Scholar
  41. 41.
    Yao Y, Huang JZ, Chen L, Chen Y, Li X. In vivo and in vitro studies on the roles of p38 mitogen-activated protein kinase and NADPH-cytochrome P450 reductase in Alzheimer’s disease. Exp Ther Med 2017, 14: 4755–4760.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Schupf N, Lee JH, Pang D, Zigman WB, Tycko B, Krinsky-McHale S, et al. Epidemiology of estrogen and dementia in women with Down syndrome. Free Radic Biol Med 2018, 114: 62–68.CrossRefPubMedGoogle Scholar
  43. 43.
    Goodman Y, Bruce AJ, Cheng B, Mattson MP. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem 1996, 66: 1836–1844.CrossRefPubMedGoogle Scholar
  44. 44.
    Luine VN. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp Neurol 1985, 89: 484–490.CrossRefPubMedGoogle Scholar
  45. 45.
    Lambert JC, Harris JM, Mann D, Lemmon H, Coates J, Cumming A, et al. Are the estrogen receptors involved in Alzheimer’s disease? Neurosci Lett 2001, 306: 193–197.CrossRefPubMedGoogle Scholar
  46. 46.
    Behl C, Widmann M, Trapp T, Holsboer F. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun 1995, 216: 473–482.CrossRefPubMedGoogle Scholar
  47. 47.
    Bruce-Keller AJ, Keeling JL, Keller JN, Huang FF, Camondola S, Mattson MP. Antiinflammatory effects of estrogen on microglial activation. Endocrinology 2000, 141: 3646–3656.CrossRefPubMedGoogle Scholar
  48. 48.
    Fester L, Prange-Kiel J, Jarry H, Rune GM. Estrogen synthesis in the hippocampus. Cell Tissue Res 2011, 345: 285–294.CrossRefPubMedGoogle Scholar
  49. 49.
    Mukai H, Kimoto T, Hojo Y, Kawato S, Murakami G, Higo S, et al. Modulation of synaptic plasticity by brain estrogen in the hippocampus. Biochim Biophys Acta 2010, 1800: 1030–1044.CrossRefPubMedGoogle Scholar
  50. 50.
    Grassi S, Tozzi A, Costa C, Tantucci M, Colcelli E, Scarduzio M, et al. Neural 17beta-estradiol facilitates long-term potentiation in the hippocampal CA1 region. Neuroscience 2011, 192: 67–73.CrossRefPubMedGoogle Scholar
  51. 51.
    Christensen A, Pike CJ. Age-dependent regulation of obesity and Alzheimer-related outcomes by hormone therapy in female 3xTg-AD mice. PLoS One 2017, 12: e0178490.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Wroolie TE, Kenna HA, Williams KE, Rasgon NL. Cognitive effects of hormone therapy continuation or discontinuation in a sample of women at risk for Alzheimer disease. Am J Geriatr Psychiatry 2015, 23: 1117–1126.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Lan YL, Zhao J, Li S. Update on the neuroprotective effect of estrogen receptor alpha against Alzheimer’s disease. J Alzheimers Dis 2015, 43: 1137–1148.CrossRefPubMedGoogle Scholar
  54. 54.
    Pratap UP, Patil A, Sharma HR, Hima L, Chockalingam R, Hariharan MM, et al. Estrogen-induced neuroprotective and anti-inflammatory effects are dependent on the brain areas of middle-aged female rats. Brain Res Bull 2016, 124: 238–253.CrossRefPubMedGoogle Scholar
  55. 55.
    Huff MO, Todd SL, Smith AL, Elpers JT, Smith AP, Murphy RD, et al. Arsenite and Cadmium activate MAPK/ERK via membrane estrogen receptors and G-protein coupled estrogen receptor signaling in human lung adenocarcinoma cells. Toxicol Sci 2016, 152: 62–71.CrossRefPubMedGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of PhysiologyShanxi Medical UniversityTaiyuanChina
  2. 2.Department of Microbiology and ImmunologyShanxi Medical UniversityTaiyuanChina
  3. 3.Department of PhysiologyChangzhi Medical CollegeChangzhiChina

Personalised recommendations