Skip to main content

Advertisement

SpringerLink
Log in

Sex Dimorphism Profile of Alzheimer’s Disease-Type Pathologies in an APP/PS1 Mouse Model

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is the most common form of dementia among the elderly, characterized by parenchymal and vascular beta-amyloid (Aβ) burden, tau pathology, neuroinflammation, and loss of neurons and synapses. There is a clear sex difference in the prevalence of AD. However, sex differences in AD-type pathologies have not been systematically documented. Applying 12-month-old female and male APP/PS1 mice as a model, we investigated the sex dimorphism in these major pathological indices. Compared with male APP/PS1 mice, the females exhibited higher parenchymal Aβ burdens, with the sex difference in hippocampus being the most significant. Female APP/PS1 mice had more severe cerebral amyloid angiopathy and subsequent microhemorrhage. In addition, female APP/PS1 mice also showed higher levels of phosphorylated tau and proinflammatory cytokines, more severe astrocytosis and microgliosis, and greater neuronal and synaptic degenerations. The present study systematically described a sex dimorphism in AD-type pathologic indices, suggesting that gender should be taken into account in designing studies involving these pathological indices and when interpreting the relevant findings in those studies.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  • Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bachman DL, Wolf PA, Linn R, Knoefel JE, Cobb J, Belanger A, D’Agostino RB, White LR (1992) Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study. Neurology 42:115–119

    Article  PubMed  CAS  Google Scholar 

  • Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA (2005) Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 62:685–691

    Article  PubMed  Google Scholar 

  • Benilova I, Karran E, De Strooper B (2012) The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15:349–357

    Article  PubMed  CAS  Google Scholar 

  • Brunden KR, Trojanowski JQ, Lee VM (2009) Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies. Nat Rev Drug Discov 8:783–793

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158

    Article  PubMed  Google Scholar 

  • Callahan MJ, Lipinski WJ, Bian F, Durham RA, Pack A, Walker LC (2001) Augmented senile plaque load in aged female beta-amyloid precursor protein-transgenic mice. Am J Pathol 158:1173–1177

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Carroll JC, Rosario ER, Kreimer S, Villamagna A, Gentzschein E, Stanczyk FZ, Pike CJ (2010) Sex differences in beta-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure. Brain Res 1366:233–245

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Casserly I, Topol E (2004) Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet 363:1139–1146

    Article  PubMed  CAS  Google Scholar 

  • Charidimou A, Gang Q, Werring DJ (2012) Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 83:124–137

    Article  PubMed  Google Scholar 

  • Fleisher A, Grundman M, Jack CR Jr, Petersen RC, Taylor C, Kim HT, Schiller DH, Bagwell V, Sencakova D, Weiner MF, DeCarli C, DeKosky ST, van Dyck CH, Thal LJ, Alzheimer’s Disease Cooperative Study (2005) Sex, apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment. Arch Neurol 62:953–957

    Article  PubMed  Google Scholar 

  • Ghebremedhin E, Schultz C, Thal DR, Rub U, Ohm TG, Braak E, Braak H (2001) Gender and age modify the association between APOE and AD-related neuropathology. Neurology 56:1696–1701

    Article  PubMed  CAS  Google Scholar 

  • Goedert M, Spillantini MG, Crowther RA (1991) Tau proteins and neurofibrillary degeneration. Brain Pathol 1:279–286

    Article  PubMed  CAS  Google Scholar 

  • Greig NH, Mattson MP, Perry T, Chan SL, Giordano T, Sambamurti K, Rogers JT, Ovadia H, Lahiri DK (2004) New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists. Ann N Y Acad Sci 1035:290–315

    Article  PubMed  CAS  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto M, Rockenstein E, Crews L, Masliah E (2003) Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromolecular Med 4:21–36

    Article  PubMed  CAS  Google Scholar 

  • Hebert LE, Scherr PA, McCann JJ, Beckett LA, Evans DA (2001) Is the risk of developing Alzheimer’s disease greater for women than for men? Am J Epidemiol 153:132–136

    Article  PubMed  CAS  Google Scholar 

  • Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG (1994) Estrogen replacement therapy in older women. Comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch Neurol 51:896–900

    Article  PubMed  CAS  Google Scholar 

  • Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28:8354–8360

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y, Mughal M, Rebeck GW, LaFerla FM, Mattson MP, Iwata N, Saido TC, Klein WL, Duff KE, Aisen PS, Matsuoka Y (2008) Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res 1216:92–103

    Article  PubMed  CAS  Google Scholar 

  • Hogervorst E, Boshuisen M, Riedel W, Willeken C, Jolles J (1999) 1998 Curt P. Richter Award. The effect of hormone replacement therapy on cognitive function in elderly women. Psychoneuroendocrinology 24:43–68

    Article  PubMed  CAS  Google Scholar 

  • Jorm AF, Jolley D (1998) The incidence of dementia: a meta-analysis. Neurology 51:728–733

    Article  PubMed  CAS  Google Scholar 

  • Jucker M, Heppner FL (2008) Cerebral and peripheral amyloid phagocytes—an old liaison with a new twist. Neuron 59:8–10

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712

    Article  PubMed  CAS  Google Scholar 

  • LeBlanc ES, Janowsky J, Chan BK, Nelson HD (2001) Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 285:1489–1499

    Article  PubMed  CAS  Google Scholar 

  • Morinaga A, Hirohata M, Ono K, Yamada M (2007) Estrogen has anti-amyloidogenic effects on Alzheimer’s beta-amyloid fibrils in vitro. Biochem Biophys Res Commun 359:697–702

    Article  PubMed  CAS  Google Scholar 

  • Morinaga A, Ono K, Takasaki J, Ikeda T, Hirohata M, Yamada M (2011) Effects of sex hormones on Alzheimer’s disease-associated beta-amyloid oligomer formation in vitro. Exp Neurol 228:298–302

    Article  PubMed  CAS  Google Scholar 

  • Paganini-Hill A (1996) Oestrogen replacement therapy and Alzheimer’s disease. Br J Obstet Gynaecol 103(Suppl 13):80–86

    PubMed  Google Scholar 

  • Pilote L, Dasgupta K, Guru V, Humphries KH, McGrath J, Norris C, Rabi D, Tremblay J, Alamian A, Barnett T, Cox J, Ghali WA, Grace S, Hamet P, Ho T, Kirkland S, Lambert M, Libersan D, O’Loughlin J, Paradis G, Petrovich M, Tagalakis V (2007) A comprehensive view of sex-specific issues related to cardiovascular disease. CMAJ 176:S1–S44

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ruitenberg A, Ott A, van Swieten JC, Hofman A, Breteler MM (2001) Incidence of dementia: does gender make a difference? Neurobiol Aging 22:575–580

    Article  PubMed  CAS  Google Scholar 

  • Salehi A, Gonzalez Martinez V, Swaab DF (1998) A sex difference and no effect of ApoE type on the amount of cytoskeletal alterations in the nucleus basalis of Meynert in Alzheimer’s disease. Neurobiol Aging 19:505–510

    Article  PubMed  CAS  Google Scholar 

  • Sandberg G, Stewart W, Smialek J, Troncoso JC (2001) The prevalence of the neuropathological lesions of Alzheimer’s disease is independent of race and gender. Neurobiol Aging 22:169–175

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Shughrue PJ, Lane MV, Merchenthaler I (1997) Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol 388:507–525

    Article  PubMed  CAS  Google Scholar 

  • Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (2004) The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 62:1984–1989

    Article  PubMed  CAS  Google Scholar 

  • Vest RS, Pike CJ (2013) Gender, sex steroid hormones, and Alzheimer’s disease. Horm Behav 63:301–307

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18:311–324

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Tanila H, Puolivali J, Kadish I, van Groen T (2003) Gender differences in the amount and deposition of amyloidbeta in APPswe and PS1 double transgenic mice. Neurobiol Dis 14:318–327

    Article  PubMed  CAS  Google Scholar 

  • Wang YJ, Wang X, Lu JJ, Li QX, Gao CY, Liu XH, Sun Y, Yang M, Lim Y, Evin G, Zhong JH, Masters C, Zhou XF (2011) p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. J Neurosci 31:2292–2304

    Article  PubMed  CAS  Google Scholar 

  • Wenk GL (2003) Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry 64(Suppl 9):7–10

    PubMed  Google Scholar 

  • Xing Y, Wei C, Chu C, Zhou A, Li F, Wu L, Song H, Zuo X, Wang F, Qin W, Li D, Tang Y, Jia XF, Jia J (2012) Stage-specific gender differences in cognitive and neuropsychiatric manifestations of vascular dementia. Am J Alzheimers Dis Other Demen 27:433–438

    Article  PubMed  Google Scholar 

  • Yue M, Hanna A, Wilson J, Roder H, Janus C (2011) Sex difference in pathology and memory decline in rTg4510 mouse model of tauopathy. Neurobiol Aging 32:590–603

    Article  PubMed  CAS  Google Scholar 

  • Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JC, Cache County Memory Study I (2002) Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA 288:2123–2129

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81471296, 81200988).

Author Contributions

YJW and XQY conceived the project and SSJ, XLB, and YHL designed research; SSJ, XQY, QHW, CZ, and LLS performed behavioral testing; SSJ, XLB, QHW, and CZ performed pathological staining and Western blotting; SSJ, CHL, and YRW performed image acquisition; LLS, XLB, and YHL performed ELISA; SSJ, XLB, and YHL analyzed data; SSJ, YJW, and YHL wrote the manuscript.

Author information

Authors and Affiliations

  1. Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China

    Shu-Sheng Jiao, Xian-Le Bu, Yu-Hui Liu, Chi Zhu, Qing-Hua Wang, Lin-Lin Shen, Cheng-Hui Liu, Ye-Ran Wang, Xiu-Qing Yao & Yan-Jiang Wang

Authors
  1. Shu-Sheng Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xian-Le Bu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qing-Hua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lin-Lin Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cheng-Hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ye-Ran Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiu-Qing Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yan-Jiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yan-Jiang Wang.

Additional information

Shu-Sheng Jiao, Xian-Le Bu, Yu-Hui Liu are equal first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 528 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiao, SS., Bu, XL., Liu, YH. et al. Sex Dimorphism Profile of Alzheimer’s Disease-Type Pathologies in an APP/PS1 Mouse Model. Neurotox Res 29, 256–266 (2016). https://doi.org/10.1007/s12640-015-9589-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-015-9589-x

Keywords

Search

Navigation