Atherosclerosis and apolipoprotein E ε4 (APOE4) genotype are risk factors for Alzheimer’s disease (AD) and cardiovascular disease (CVD). Sex differences exist in prevalence and manifestation of both diseases. We investigated sex differences respective to aging, focusing on cognitive parameters in apoE4 and apoE knockout (ko) mouse models of AD and CVD. Presynaptic density and neurogenesis were investigated immunohistochemically in male and female apoE4, apoE ko, and wild-type mice. Middle-aged female apoE4 mice showed decreased presynaptic density in the inner molecular layer of the dentate gyrus of the hippocampus. Middle-aged female apoE ko mice showed a trend towards increased neurogenesis in the hippocampus compared with wild-type mice. No differences in these parameters could be observed in middle-aged male mice. Specific harmful interactions between apoE4 and estrogen could be responsible for decreased presynaptic density in female apoE4 mice. The trend of increased neurogenesis found in female apoE ko mice supports previous studies suggesting that temporarily increased amount of synaptic contacts and/or neurogenesis is a compensatory mechanism for synaptic failure. To our knowledge, no other studies investigating presynaptic density in aging female apoE4 or apoE ko mice are available. Sex-specific differences between APOE genotypes could account for some sex differences in AD and CVD. 1. Introduction Western society is currently faced with an increasing incidence of vascular diseases such as hypercholesterolemia and atherosclerosis, mainly as a consequence of unhealthy lifestyle habits, an increase in obesity, and an aging population. Vascular diseases and obesity are risk factors for disorders that affect cognitive function such as diabetes mellitus, stroke, vascular dementia, and Alzheimer’s disease (AD) [1, 2]. Sex differences exist in both AD and cardiovascular disease (CVD). While women have a higher risk for AD, men are generally more affected by CVD [3]. For example, men are more prone to develop high serum cholesterol levels at a younger age than (premenopausal) women [4, 5]. Most of these sex differences disappear, however, when women reach menopause, when they equal and even surpass men in the prevalence of CVD [3, 6]. However, differences in the manifestation of CVD remain. For example, while men have thicker atherosclerotic plaques in the large coronary arteries, women tend to have more diffuse plaques that also impair the smaller microvasculature [4, 5, 7]. One factor influencing the prevalence of both vascular and Alzheimer’s
References
[1]
M. Kivipelto, T. Ngandu, L. Fratiglioni et al., “Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease,” Archives of Neurology, vol. 62, no. 10, pp. 1556–1560, 2005.
[2]
J. A. Luchsinger, C. Reitz, L. S. Honig, M. X. Tang, S. Shea, and R. Mayeux, “Aggregation of vascular risk factors and risk of incident Alzheimer disease,” Neurology, vol. 65, no. 4, pp. 545–551, 2005.
[3]
L. Pilote, K. Dasgupta, V. Guru, K. H. Humphries, J. McGrath, et al., “A comprehensive view of sex-specific issues related to cardiovascular disease,” Canadian Medical Association Journal, vol. 176, pp. S1–S44, 2007.
[4]
A. H. E. M. Maas, Y. T. Van Der Schouw, V. Regitz-Zagrosek, E. Swahn, Y. E. Appelman, et al., “Red alert for womens heart: the urgent need for more research and knowledge on cardiovascular disease in women,” European Heart Journal, vol. 32, pp. 1362–1368, 2011.
[5]
A. H. E. M. Maas and Y. E. A. Appelman, “Gender differences in coronary heart disease,” Netherlands Heart Journal, vol. 18, no. 12, pp. 598–603, 2010.
[6]
M. Abbey, A. Owen, M. Suzakawa, P. Roach, and P. J. Nestel, “Effects of menopause and hormone replacement therapy on plasma lipids, lipoproteins and LDL-receptor activity,” Maturitas, vol. 33, no. 3, pp. 259–269, 1999.
[7]
A. C. Villablanca, M. Jayachandran, and C. Banka, “Atherosclerosis and sex hormones: current concepts,” Clinical Science, vol. 119, no. 12, pp. 493–513, 2010.
[8]
E. H. Corder, A. M. Saunders, W. J. Strittmatter et al., “Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families,” Science, vol. 261, no. 5123, pp. 921–923, 1993.
[9]
W. J. Strittmatter, A. M. Saunders, D. Schmechel et al., “Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 5, pp. 1977–1981, 1993.
[10]
L. A. Farrer, L. A. Cupples, J. L. Haines et al., “Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis,” Journal of the American Medical Association, vol. 278, no. 16, pp. 1349–1356, 1997.
[11]
C. J. Packard, R. G. J. Westendorp, D. J. Stott et al., “Association between apolipoprotein E4 and cognitive decline in elderly adults,” Journal of the American Geriatrics Society, vol. 55, no. 11, pp. 1777–1785, 2007.
[12]
J. D. Flory, S. B. Manuck, R. E. Ferrell, C. M. Ryan, and M. F. Muldoon, “Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults,” American Journal of Medical Genetics, vol. 96, no. 6, pp. 707–711, 2000.
[13]
M. W. Bondi, D. P. Salmon, A. U. Monsch et al., “Episodic memory changes are associated with the APOE-ε4 allele in nondemented older adults,” Neurology, vol. 45, no. 12, pp. 2203–2206, 1995.
[14]
T. Reed, D. Carmelli, G. E. Swan et al., “Lower cognitive performance in normal older adult male twins carrying the apolipoprotein E ε4 allele,” Archives of Neurology, vol. 51, no. 12, pp. 1189–1192, 1994.
[15]
J. R. Lynch, D. Morgan, J. Mance, W. D. Matthew, and D. T. Laskowitz, “Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response,” Journal of Neuroimmunology, vol. 114, no. 1-2, pp. 107–113, 2001.
[16]
M. Miyata and J. D. Smith, “Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloid peptides,” Nature Genetics, vol. 14, no. 1, pp. 55–61, 1996.
[17]
Y. Huang, “Mechanisms linking apolipoprotein e isoforms with cardiovascular and neurological diseases,” Current Opinion in Lipidology, vol. 21, no. 4, pp. 337–345, 2010.
[18]
D. K. Lahiri, B. Maloney, and R. S. Larry, “Genomics of brain aging: apolipoprotein E,” in Encyclopedia of Neuroscience, pp. 685–693, Academic Press, Oxford, UK, 2009.
[19]
J. Davignon, “Apolipoprotein E and atherosclerosis beyond lipid effect,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 2, pp. 267–269, 2005.
[20]
R. W. Mahley, “Apolipoprotein E: cholesterol transport protein with expanding role in cell biology,” Science, vol. 240, no. 4852, pp. 622–630, 1988.
[21]
J. S. Gong, M. Kobayashi, H. Hayashi et al., “Apolipoprotein E (ApoE) isoform-dependent lipid release from astrocytes prepared from human ApoE3 and ApoE4 knock-in mice,” Journal of Biological Chemistry, vol. 277, no. 33, pp. 29919–29926, 2002.
[22]
R. D. Bell, A. P. Sagare, A. E. Friedman et al., “Transport pathways for clearance of human Alzheimer's amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 5, pp. 909–918, 2007.
[23]
E. Klann and T. E. Dever, “Biochemical mechanisms for translational regulation in synaptic plasticity,” Nature Reviews Neuroscience, vol. 5, no. 12, pp. 931–942, 2004.
[24]
N. A. Johnson, G. H. Jahng, M. W. Weiner et al., “Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience,” Radiology, vol. 234, no. 3, pp. 851–859, 2005.
[25]
K. Hirao, T. Ohnishi, Y. Hirata et al., “The prediction of rapid conversion to Alzheimer's disease in mild cognitive impairment using regional cerebral blood flow SPECT,” NeuroImage, vol. 28, no. 4, pp. 1014–1021, 2005.
[26]
D. Bartrés-Faz, C. Junqué, P. Moral, A. López-Alomar, J. Sánchez-Aldeguer, and I. C. Clemente, “Apolipoprotein E gender effects on cognitive performance in age-associated memory impairment,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 14, no. 1, pp. 80–83, 2002.
[27]
E. L. Mortensen and P. H？gh, “A gender difference in the association between APOE genotype and age-related cognitive decline,” Neurology, vol. 57, no. 1, pp. 89–95, 2001.
[28]
P. M. Bretsky, J. G. Buckwalter, T. E. Seeman et al., “Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease,” Alzheimer Disease and Associated Disorders, vol. 13, no. 4, pp. 216–221, 1999.
[29]
J. Raber, D. Wong, M. Buttini et al., “Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 18, pp. 10914–10919, 1998.
[30]
A. Bour, J. Grootendorst, E. Vogel et al., “Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks,” Behavioural Brain Research, vol. 193, no. 2, pp. 174–182, 2008.
[31]
K. Yaffe, M. Haan, A. Byers, C. Tangen, and L. Kuller, “Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction,” Neurology, vol. 54, no. 10, pp. 1949–1953, 2000.
[32]
J. H. Kang and F. Grodstein, “Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline,” Neurobiology of Aging, vol. 33, pp. 1129–1137, 2012.
[33]
B. P. Nathan, A. G. Barsukova, F. Shen, M. McAsey, and R. G. Struble, “Estrogen facilitates neurite extension via apolipoprotein E in cultured adult mouse cortical neurons,” Endocrinology, vol. 145, no. 7, pp. 3065–3073, 2004.
[34]
J. Levin-Allerhand, B. S. McEwen, C. E. Lominska, D. B. Lubahn, K. S. Korach, and J. D. Smith, “Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments,” Journal of Neurochemistry, vol. 79, no. 4, pp. 796–803, 2001.
[35]
K. B. J. Franklin and G. Paxinos, The Mouse Brain in Stereotaxic Coordinates, Academic Press, San Diego, Calif, USA, 1997.
[36]
O. Levi, A. L. Jongen-Relo, J. Feldon, and D. M. Michaelson, “Brain area- and isoform-specific inhibition of synaptic plasticity by apoE4,” Journal of the Neurological Sciences, vol. 229-230, pp. 241–248, 2005.
[37]
I. Veinbergs, M. Mallory, M. Mante, E. Rockenstein, J. R. Gilbert, and E. Masliah, “Differential neurotrophic effects of apolipoprotein E in aged transgenic mice,” Neuroscience Letters, vol. 265, no. 3, pp. 218–222, 1999.
[38]
S. W. Scheff, D. A. Price, F. A. Schmitt, S. T. Dekosky, and E. J. Mufson, “Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment,” Neurology, vol. 68, no. 18, pp. 1501–1508, 2007.
[39]
S. W. Scheff, D. A. Price, F. A. Schmitt, and E. J. Mufson, “Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment,” Neurobiology of Aging, vol. 27, no. 10, pp. 1372–1384, 2006.
[40]
P. H. Reddy, G. Mani, B. S. Park et al., “Differential loss of synaptic proteins in Alzheimer's disease: implications for synaptic dysfunction,” Journal of Alzheimer's Disease, vol. 7, no. 2, pp. 103–117, 2005.
[41]
M. P. Witter, “The perforant path: projections from the entorhinal cortex to the dentate gyrus,” Progress in Brain Research, vol. 163, pp. 43–61, 2007.
[42]
A. Dimoka, S. H. Courellis, V. Z. Marmarelis, and T. W. Berger, “Modeling the nonlinear dynamic interactions of afferent pathways in the dentate gyrus of the hippocampus,” Annals of Biomedical Engineering, vol. 36, no. 5, pp. 852–864, 2008.
[43]
T. Den Heijer, L. J. Launer, N. D. Prins et al., “Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe,” Neurology, vol. 64, no. 2, pp. 263–267, 2005.
[44]
E. S. C. Korf, L. R. White, P. Scheltens, and L. J. Launer, “Midlife blood pressure and the risk of hippocampal atrophy: the Honolulu Asia aging study,” Hypertension, vol. 44, no. 1, pp. 29–34, 2004.
[45]
A. M. Stranahan and M. P. Mattson, “Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer's disease,” Neural Plasticity, vol. 2010, Article ID 108190, 8 pages, 2010.
[46]
M. A. Yassa, L. T. Muftuler, and C. E. L. Stark, “Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 28, pp. 12687–12691, 2010.
[47]
D. J. Froc, B. Eadie, A. M. Li, K. Wodtke, M. Tse, and B. R. Christie, “Reduced synaptic plasticity in the lateral perforant path input to the dentate gyrus of aged C57BL/6 mice,” Journal of Neurophysiology, vol. 90, no. 1, pp. 32–38, 2003.
[48]
A. H. Gazzaley, S. J. Siegel, J. H. Kordower, E. J. Mufson, and J. H. Morrison, “Circuit-specific alterations of N-methyl-D-aspartate receptor subunit 1 in the dentate gyrus of aged monkeys,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 7, pp. 3121–3125, 1996.
[49]
G. Li, N. Bien-Ly, Y. Andrews-Zwilling et al., “GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice,” Cell Stem Cell, vol. 5, no. 6, pp. 634–645, 2009.
[50]
D. Jansen, C. I. F. Janssen, T. Vanmierlo, T. D, et al., “Cholesterol and synaptic compensatory mechanisms in Alzheimer's Disease mice brain during aging,” Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 813–826, 2012.
[51]
O. Levi and D. M. Michaelson, “Environmental enrichment stimulates neurogenesis in apolipoprotein E3 and neuronal apoptosis in apolipoprotein E4 transgenic mice,” Journal of Neurochemistry, vol. 100, no. 1, pp. 202–210, 2007.
[52]
K. Jin, A. L. Peel, X. O. Mao et al., “Increased hippocampal neurogenesis in Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 1, pp. 343–347, 2004.
[53]
O. Liraz, A. Haas, and D. M. Michaelson ", “ApoE4 induces synaptic deficits in young mice,” in Alzheimer’s and Parkinson’s Diseases: Advances, Concepts and New Challenges, R. M. Nitsch, A. Fisher, M. Windisch, and I. Hanin, Eds., vol. 8, supplement 1, S. Karger/Medical and Scientific Publishers, Barcelona, Spain, 2011.
[54]
K. Boekhoorn, M. Joels, and P. J. Lucassen, “Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus,” Neurobiology of Disease, vol. 24, no. 1, pp. 1–14, 2006.
[55]
M. H. Donovan, U. Yazdani, R. D. Norris, D. Games, D. C. German, and A. J. Eisch, “Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease,” Journal of Comparative Neurology, vol. 495, no. 1, pp. 70–83, 2006.
[56]
P. H. Wen, P. R. Hof, X. Chen et al., “The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice,” Experimental Neurology, vol. 188, no. 2, pp. 224–237, 2004.
[57]
K. Jin, V. Galvan, L. Xie et al., “Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APP Sw,Ind) mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 36, pp. 13363–13367, 2004.
[58]
M. E. Mendelsohn and R. H. Karas, “The protective effects of estrogen on the cardiovascular system,” The New England Journal of Medicine, vol. 340, no. 23, pp. 1801–1811, 1999.
[59]
V. Vaccarino, L. Badimon, R. Corti, et al., “Ischaemic heart disease in women: are there sex differences in pathophysiology and risk factors? Position Paper from the Working Group on Coronary Pathophysiology and Microcirculation of the European Society of Cardiology,” Cardiovascular Research, vol. 90, pp. 9–17, 2011.
[60]
K. Kublickiene and L. Luksha, “Gender and the endothelium,” Pharmacological Reports, vol. 60, no. 1, pp. 49–60, 2008.
[61]
J. C. Lambert, N. Coyle, and C. Lendon, “The allelic modulation of apolipoprotein E expression by oestrogen: potential relevance for Alzheimer's disease,” Journal of Medical Genetics, vol. 41, no. 2, pp. 104–112, 2004.
[62]
M. X. Tang, D. Jacobs, Y. Stern et al., “Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease,” The Lancet, vol. 348, no. 9025, pp. 429–432, 1996.
[63]
C. Kawas, S. Resnick, A. Morrison et al., “A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: The Baltimore Longitudinal Study of Aging,” Neurology, vol. 48, no. 6, pp. 1517–1521, 1997.
[64]
M. I. Geerlings, A. Ruitenberg, J. C. M. Witteman et al., “Reproductive period and risk of dementia in postmenopausal women,” Journal of the American Medical Association, vol. 285, no. 11, pp. 1475–1481, 2001.
[65]
J. Raber, G. Bongers, A. LeFevour, M. Buttini, and L. Mucke, “Androgens protect against apolipoprotein E4-induced cognitive deficits,” Journal of Neuroscience, vol. 22, no. 12, pp. 5204–5209, 2002.
[66]
Y. Guo, C. Zhang, X. Du, U. Nair, and T. J. Yoo, “Morphological and functional alterations of the cochlea in apolipoprotein E gene deficient mice,” Hearing Research, vol. 208, no. 1-2, pp. 54–67, 2005.
[67]
L. V. D'Uscio, T. A. Baker, C. B. Mantilla et al., “Mechanism of endothelial dysfunction in apolipoprotein E-deficient mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 6, pp. 1017–1022, 2001.
[68]
Y. X. Wang, “Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice,” Neurobiology of Aging, vol. 26, no. 3, pp. 309–316, 2005.
[69]
C. G. Specht and R. Schoepfer, “Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice,” BMC Neuroscience, vol. 2, article 11, 2001.
[70]
I. Gureviciene, K. Gurevicius, and H. Tanila, “Role of α-synuclein in synaptic glutamate release,” Neurobiology of Disease, vol. 28, no. 1, pp. 83–89, 2007.
[71]
L. Yavich, H. Tanila, S. Veps？l？inen, and P. J？k？l？, “Role of α-synuclein in presynaptic dopamine recruitment,” Journal of Neuroscience, vol. 24, no. 49, pp. 11165–11170, 2004.
[72]
L. Yavich, P. J？k？l？, and H. Tanila, “Abnormal compartmentalization of norepinephrine in mouse dentate gyrus in α-synuclein knockout and A30P transgenic mice,” Journal of Neurochemistry, vol. 99, no. 3, pp. 724–732, 2006.
