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.
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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
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
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
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
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
Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158
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
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
Casserly I, Topol E (2004) Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet 363:1139–1146
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
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
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
Goedert M, Spillantini MG, Crowther RA (1991) Tau proteins and neurofibrillary degeneration. Brain Pathol 1:279–286
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
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356
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
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
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
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
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
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
Jorm AF, Jolley D (1998) The incidence of dementia: a meta-analysis. Neurology 51:728–733
Jucker M, Heppner FL (2008) Cerebral and peripheral amyloid phagocytes—an old liaison with a new twist. Neuron 59:8–10
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
LeBlanc ES, Janowsky J, Chan BK, Nelson HD (2001) Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 285:1489–1499
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
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
Paganini-Hill A (1996) Oestrogen replacement therapy and Alzheimer’s disease. Br J Obstet Gynaecol 103(Suppl 13):80–86
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
Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344
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
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
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
Schnabel J (2011) Amyloid: little proteins, big clues. Nature 475:S12–S14
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
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
Vest RS, Pike CJ (2013) Gender, sex steroid hormones, and Alzheimer’s disease. Horm Behav 63:301–307
Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18:311–324
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
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
Wenk GL (2003) Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry 64(Suppl 9):7–10
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
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
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
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.
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Shu-Sheng Jiao, Xian-Le Bu, Yu-Hui Liu are equal first authors.
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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
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DOI: https://doi.org/10.1007/s12640-015-9589-x