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Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: Increased susceptibility of females
Open accessAbstract
Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (ɛ 2 , ɛ 3 , and ɛ 4 ). Compared with APOE ɛ 2 and ɛ 3 , APOE ɛ 4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer’s disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE ɛ 4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE ɛ 4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE ɛ 4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits.
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“The APOE4 allele is a major genetic risk factor for late-onset AD and was previously shown to accelerate AD progression in humans and in mouse models 6-11 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [9]
In the citing paper
“The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD).”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [9]
In the citing paper
“Although the genetic association of apoE4 and, more specifically, apoE4[L28P] with LOAD has been established, previous attempts to model this effect in experimental animals have yielded conflicting results.”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [62]
In the citing paper
“In contrast, in another study, transgenic WT apoE4 mice lacking endogenous mouse apoE and expressing human apoE transgenes in neurons, under the control of the neuron-specific enolase promoter, showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age compared with neuron-specific enolase-apoE3 transgenic mice and control non-transgenic mice (62)”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [62]
In the citing paper
“and were more severely impaired in learning and memory (Hartman et al., 2001; Raber et al., 1998; Raber et al., 2000).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Raber et al., 1998
In the citing paper
“These mice have impairments in learning and memory [50], as well as a loss of dendritic spines in primary neurons and in the hippocampus and cortex [21].”
From Arf4 Determines Dentate Gyrus-Mediated Pattern Separation by Regulating Dendritic Spine Development (2012) · cites this paper as [50]
In the citing paper
“Some studies show no significant cognitive impairments compared to either wild type or human apoE3 expressing mice (Raber et al., 1998, Grootendorst et al., 2005, Hartman et al., 2001, van Meer et al., 2007)”
From Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner (2014) · cites this paper as Raber et al., 1998
In the citing paper
“apoE isoform specific sex differences in behavior have been previously shown (Raber et al., 1998, Raber et al., 2000).”
From Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner (2014) · cites this paper as Raber et al., 1998
In the citing paper
“For example, both apoE4 transgenic and apoE4-KI mice show age- and sex-dependent learning and memory deficits in the absence of Aβ accumulation, as compared to apoE3 transgenic and apoE3-KI mice [68–71].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [68]
Citations
Cites
Developments of a water-maze procedure for studying spatial learning in the rat
Morris, R. (1984) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(84)90007-4 · Cited by 7,180
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028
Self-citationPiedrahita, J. A., Zhang, S. H., Hagaman, J. R., Oliver, P. M., & Maeda, N. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.10.4471 · Cited by 944
Testosterone influences spatial cognition in older men.
Janowsky, J. S., Oviatt, S. K., & ORWOLL, E. S. (1994) · Behavioral Neuroscience · doi:10.1037//0735-7044.108.2.325 · Cited by 578
Apolipoprotein E and Alzheimer's disease
Strittmatter, W. J., & Roses, A. D. (1996) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.19.030196.000413 · Cited by 477
Testosterone influences spatial cognition in older men.
Janowsky, J. S., Oviatt, S. K., & ORWOLL, E. S. (1994) · Behavioral Neuroscience · doi:10.1037/0735-7044.108.2.325 · Cited by 424
Hecker, K. H., & Roux, K. H. (1996) · BioTechniques · doi:10.2144/19962003478 · Cited by 415
Neurodegeneration in the Central Nervous System of apoE-Deficient Mice
Masliah, E., Mallory, M. E., Ge, N., Alford, M. F., Veinbergs, I., & Roses, A. D. (1995) · Experimental Neurology · doi:10.1006/exnr.1995.1088 · Cited by 402
Estrogen use and verbal memory in healthy postmenopausal women
KAMPEN, D. L., & SHERWIN, B. B. (1994) · Obstetrics & Gynecology · doi:10.1097/00006250-199406000-00017 · Cited by 394
Forss‐Petter, S., Danielson, P. E., Catsicas, S., Battenberg, E., Price, J. A., Nerenberg, M. I., & Sutcliffe, G. (1990) · Neuron · doi:10.1016/0896-6273(90)90308-3 · Cited by 368
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Items 101–200 of 363
Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice
Hamanaka, H. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.3.353 · Cited by 99
Veinbergs, I., Mallory, M. E., Sagara, Y., & Masliah, E. (2000) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2000.01308.x · Cited by 96
“…1994; Masliah et al., 1995a; Buttini et al., 1999; Veinbergs et al., 1999), accompanied by behavioural and neurophysiological alterations (Gordon et al., 1995; Masliah et al., 1996, 1997; Gozes et al., 1997; Oitzl et al., 1997; Fisher et al., 1998; Raber et al., 1998; Buttini et al., 1999).”
BackgroundAge-related accumulation of Reelin in amyloid-like deposits
Knuesel, I., Nyffeler, M., Mormède, C., Muhia, M., Meyer, U., Pietropaolo, S., Yee, B. K., Pryce, C. R., LaFerla, F. M., Marighetto, A., et al. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.08.011 · Cited by 94
EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerʼns disease
Tai, L. M., Balu, D., Avila-Munoz, E., Abdullah, L., Thomas, R., Collins, N., Valencia-Olvera, A. C., & LaDu, M. J. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r076315 · Cited by 93
The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s Disease of humans and mice
Cacciottolo, M., Christensen, A., Moser, A., Liu, J., Pike, C., Smith, C., LaDu, M., Sullivan, P., Morgan, T., Dolzhenko, E., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.10.010 · Cited by 93
“Mice were examined at age 6e7months, when the female bias in behavioral deficits emerges in the NSE-APOE mouse (Raber et al., 1998).”
MethodGianfrani, C., Troncone, R., Mugìone, P., Cosentini, E., Pascale, M. D., Faruolo, C., Senger, S., Terrazzano, G., Southwood, S., Auricchio, S., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.5.2719 · Cited by 92
The role of apolipoprotein E in Alzheimer’s disease: pharmacogenomic target selection
Saunders, A. M., Trowers, M. K., Shimkets, R. A., Blakemore, S., Crowther, D., Mansfield, T. A., Wallace, D. M., Strittmatter, W. J., & Roses, A. D. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00035-1 · Cited by 92
Liu, D.-S., Pan, X.-D., Zhang, J., Shen, H., Collins, N. C., Cole, A. M., Koster, K. P., Ben Aissa, M., Dai, X.-M., Zhou, M., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0002-2 · Cited by 99
Yu, Y. W. ‐., Lin, C., Chen, S.-P., Hong, C., & Tsai, S. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01569-x · Cited by 91
Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline
Kang, J. H., & Grodstein, F. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.10.007 · Cited by 90
“(Raber et al., 1998) Estrogen is known to modulate the expression of apolipoprotein E, and estradiol promotes synaptogenesis in response to injury via an apolipoprotein E -dependent mechanism.”
BackgroundHuang, T. L. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-090934 · Cited by 91
“ing and memory with age [101,102].”
Neurotoxic effects of apolipoprotein E4 are mediated via dysregulation of calcium homeostasis
Veinbergs, I., Everson, A., Sagara, Y., & Masliah, E. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10138 · Cited by 92
“Furthermore, compared to apoE3-transgenic (tg) and apoE-deficient mice, apoE4-tg mice show an increased susceptibility to both excitotoxin-induced and age-related neurodegeneration (Raber et al., 1998; Buttini et al., 1999).”
BackgroundArai, T., Rinninger, F., Varban, M. L., Fairchild-Huntress, V., Liang, C.-P., Chen, W., Seo, T., Deckelbaum, R. J., Huszar, D., & Tall, A. R. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.21.12050 · Cited by 86
Sex‐dependent effects of 56Fe irradiation on contextual fear conditioning in C57BL/6J mice
Villasana, L., Rosenberg, J. S., & Raber, J. (2009) · Hippocampus · doi:10.1002/hipo.20659 · Cited by 86
“Consistent with these human studies, female mice are more sensitive than male mice to effects of age (Benice et al., 2006) and apoE4 (Raber et al., 1998, 2000) on hippocampus-dependent cognitive function.”
ResultSelf-citationHashimoto, Y., Jiang, H., Niikura, T., Ito, Y., Hagiwara, A., Umezawa, K., Abe, Y., Murayama, Y., & Nishimoto, I. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-22-08401.2000 · Cited by 86
“Although ApoE4-induced neurodegeneration has not yet been clearly shown in transgenic mice (Raber et al., 1998; Sun et al., 1998), it might result from in vivo suppression of ApoE4 neurotoxicity.”
BackgroundSynaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms
Forero, D. A., Casadesús, G., Perry, G. L., & Arboleda, H. (2006) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2006.tb00439.x · Cited by 89
Brodbeck, J., Balestra, M. E., Saunders, A. M., Roses, A. D., Mahley, R. W., & Huang, Y. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709906104 · Cited by 86
Self-citationPresenile dementia syndromes: an update on taxonomy and diagnosis
Greicius, M. D. (2002) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.72.6.691 · Cited by 86
Olfactory function in apoE knockout mice
Nathan, B. P., Yost, J., Litherland, M. T., Struble, R. G., & Switzer, P. V. (2003) · Behavioural Brain Research · doi:10.1016/s0166-4328(03)00219-5 · Cited by 82
“Several previous studies have found cognitive deficit in apoE KO mice; however, these findings are controversial [1,17,18,21,23,25,37,42,44,49,55] .”
BackgroundMahley, R. W., & Huang, Y. (2006) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2006.00679.x · Cited by 84
“with or without hAPP expression (19–21), increased phosphorylated tau with neuronal expression of apoE4 (22–24), and impaired spatial learning and memory (25, 26).”
BackgroundSelf-citationMechanisms linking apolipoprotein E isoforms with cardiovascular and neurological diseases.
Huang, Y. (2010) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32833af368 · Cited by 82
Spatial Navigation and APOE in Amnestic Mild Cognitive Impairment
Laczó, J., Andel, R., Vlček, K., Macoška, V., Vyhnálek, M., Tolar, M., Bojar, M., & Hort, J. (2010) · Neurodegenerative Diseases · doi:10.1159/000321581 · Cited by 81
“but none of the studies dealt with the APOE status. Animal studies with transgenic mice revealed that the human e4 strongly affects spatial navigation and spatial learning in a Morris water maze (MWM) [”
BackgroundApoE isoforms and measures of anxiety in probable AD patients and Apoe−/− mice
Robertson, J., Curley, J., Kaye, J., Quinn, J., Pfankuch, T., & Raber, J. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.06.003 · Cited by 71
“[24] Raber J, Wong D, Buttini M, Orth M, Bellosta S, Pitas ER, et al.”
BackgroundMethodSelf-citationXu, Q., Brecht, W. J., Weisgraber, K. H., Mahley, R. W., & Huang, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311256200 · Cited by 80
Self-citationButtini, M., Masliah, E., Yu, G.-Q., Palop, J. J., Chang, S., Bernardo, A., Lin, C., Wyss-Coray, T., Huang, Y., & Mucke, L. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.090973 · Cited by 80
“In such models, apoE4 is also more susceptible to C-terminal proteolytic cleavage than apoE3,(30,34,35) depletes cytosolic androgen receptor levels,(36) and is associated with cognitive impairments.(37,38) Interestingly, apoE4 undergoes proteolytic cleavage and increases tau phosphorylation only when produced by neuro…”
BackgroundMethodSelf-citationLamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model
Heng, M. Y., Lin, S.-T., Verret, L., Huang, Y., Kamiya, S., Padiath, Q. S., Tong, Y., Palop, J. J., Huang, E. J., Ptácχek, L. J., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66737 · Cited by 78
“The PA test was used as previously described (41).”
Apolipoprotein E isoform-dependent effects on anxiety and cognition in female TR mice
Siegel, J. A., Haley, G. E., & Raber, J. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.03.002 · Cited by 82
“Although NSE-apoE4 and Apoe / male mice how higher measures of anxiety compared with wild type nd NSE-apoE3 male mice (Robertson et al., 2005), there as no genotype difference in cognitive performance in hese mice at 6 (Raber et al., 1998) or 18 mo of age (Raber t al., 2000b).”
Self-citationEffects of sex and APOE ε4 on object recognition and spatial navigation in the elderly
Berteau-Pavy, F., Park, B., & Raber, J. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.03.005 · Cited by 85
Self-citationSex- and APOE Isoform-Dependent Effects of Radiation on Cognitive Function
Villasana, L., Acevedo, S. F., Poage, C. T., & Raber, J. (2006) · Radiation Research · doi:10.1667/rr0642.1 · Cited by 74
Self-citationAβ42 neurotoxicity in primary co-cultures: effect of apoE isoform and Aβ conformation
Manelli, A. M., Bulfinch, L. C., Sullivan, P. M., & LaDu, M. J. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.05.024 · Cited by 72
“ApoE-knock out (apoE-KO) mice [60,62] have been used to assess the role of apoE in CNS function and are the background for a number of transgenic mouse lines where heterologous promoters drive the expression of human apoE [3,27,66,74,80,81].”
BackgroundLewandowski, C. T., Maldonado Weng, J., & LaDu, M. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104811 · Cited by 72
Apolipoprotein E4 and Sex Affect Neurobehavioral Performance in Primary School Children
Acevedo, S. F., Piper, B. J., Craytor, M. J., Benice, T. S., & Raber, J. (2010) · Pediatric Research · doi:10.1203/pdr.0b013e3181cb8e68 · Cited by 75
Self-citationBien-Ly, N., Andrews-Zwilling, Y., Xu, Q., Bernardo, A., Wang, C., & Huang, Y. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1018381108 · Cited by 71
“Interestingly, the premature death of hAPPFAD mice, as reported (17, 28, 34), was also similar in hAPPFAD/mEKO and hAPPFAD/ apoE4(Δ272–299)/mEKO mice (Fig.”
MethodResultJanssen, C., Jansen, D., Mutsaers, M. P. C., Dederen, P. J., Geenen, B., Mulder, M., & Kiliaan, A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0155307 · Cited by 71
“Other studies have shown spatial memory deficits in male ApoE4 mice and even more in ApoE4 female mice which have been attributed to estrogen [39,40].”
BackgroundThe generation and function of soluble apoE receptors in the CNS
Rebeck, G. W., LaDu, M. J., Estus, S., Bu, G., & Weeber, E. J. (2006) · Molecular Neurodegeneration · doi:10.1186/1750-1326-1-15 · Cited by 66
“Transgenic expression of human apoE4 has dominant negative behavioral effects [103-106], including deficits in memory tasks [103,105].”
Progress toward valid transgenic mouse models for Alzheimer’s disease
Guénette, S. Y., & Tanzi, R. E. (1999) · Neurobiology of Aging · doi:10.1016/s0197-4580(99)00042-1 · Cited by 67
Roberson, E. D., & Kao, A. W. (2009) · Cambridge University Press eBooks · doi:10.1017/cbo9780511581410.010 · Cited by 67
AR, apoE, and cognitive function
Raber, J. (2008) · Hormones and Behavior · doi:10.1016/j.yhbeh.2008.02.012 · Cited by 66
“Expression of apoE4 in Apoe−/− mice leads to age- and sexdependent impairments in spatial learning and memory (Raber et al., 1998, 2000).”
Self-citationGrootendorst, J., de Kloet, E. R., Dalm, S., & Oitzl, M. S. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00412-2 · Cited by 64
Koch, G., Di Lorenzo, F., Loizzo, S., Motta, C., Travaglione, S., Baiula, M., Rimondini, R., Ponzo, V., Bonnì, S., Toniolo, S., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-14204-3 · Cited by 64
Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease
Theendakara, V., Peters-Libeu, C. A., Bredesen, D. E., & Rao, R. V. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0757-2 · Cited by 63
Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function.
Teter, B., Xu, P., Gilbert, J. R., Roses, A. D., Galasko, D., & Cole, G. M. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10221 · Cited by 74
“The regenerative capacity of the CNS can, in principle, counteract some neurodegeneration, yet behavioral deficits are persistent in apoE4 transgenics (Raber et al., 1998, 2000; Buttini et al., 1999).”
Sex and Gender Differences in Alzheimer’s Disease: Genetic, Hormonal, and Inflammation Impacts
Kolahchi, Z., Henkel, N., Eladawi, M. A., Villarreal, E. C., Kandimalla, P., Lundh, A., McCullumsmith, R. E., & Cuevas, E. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25158485 · Cited by 66
“Preclinical work suggests that the APOE ε 4 effects on cognition impairment are modulated by sex and age and are increased in aged female mice [156].”
BackgroundMethodThe role of APOE in transgenic mouse models of AD
Balu, D., Karstens, A. J., Loukenas, E., Maldonado Weng, J., York, J. M., Valencia-Olvera, A. C., & LaDu, M. J. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134285 · Cited by 81
Grootendorst, J., de Kloet, E. R., Vossen, C., Dalm, S., & Oitzl, M. S. (2001) · Behavioural Brain Research · doi:10.1016/s0166-4328(01)00294-7 · Cited by 63
Transcription Factors Zic1 and Zic2 Bind and Transactivate the Apolipoprotein E Gene Promoter
Salero, E., Pérez‐Sen, R., Aruga, J., Giménez, C., & Zafra, F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007008200 · Cited by 61
Mortalin is regulated by APOE in hippocampus of AD patients and by human APOE in TR mice
Osorio, C., Sullivan, P. M., Dong, H., Mace, B. E., Ervin, J. F., Strittmatter, W. J., & Álzate, Ó. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.08.011 · Cited by 62
Accelerated Cell Aging in Female APOE-ε4 Carriers: Implications for Hormone Therapy Use
Jacobs, E. G., Kroenke, C. H., Lin, J., Epel, E. S., Kenna, H. A., Blackburn, E. H., & Rasgon, N. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054713 · Cited by 63
Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H
Kotredes, K. P., Oblak, A., Pandey, R. S., Lin, P. B.-C., Garceau, D., Williams, H., Uyar, A., O’Rourke, R., O’Rourke, S., Ingraham, C., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.735524 · Cited by 66
“, 2020), including the development of multiple mouse models expressing transgenes or targeted mutations (Xu et al., 1996; Raber et al., 1998; Sun et al., 1998; Knouff et al., 1999; Huber et al., 2000; Tesseur et al., 2000; Lesuisse et al., 2001; Bien-Ly et al., 2012).”
BackgroundApolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury
Crawford, F., Wood, M., Ferguson, S., Mathura, V., Gupta, P., Humphrey, J., Mouzon, B., Laporte, V., Margenthaler, E., O'Steen, B., et al. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.01.033 · Cited by 59
Genetic Evidence for Cognitive Reserve: Variations in Memory and Related Cognitive Functions
Lee, J. H. (2003) · Journal of Clinical and Experimental Neuropsychology · doi:10.1076/jcen.25.5.594.14582 · Cited by 59
“Compared with intact mice, APOE-deficient mice have lower synaptic density in cholinergic, noradrenergic, and serotinergic projections to relevant brain regions (Chapman & Michaelson, 1998) and perform worse in several types of memory tasks (Buttini et al., 1999; Dodart et al., 2000; Raber et al., 1998).”
BackgroundApoE-Dependent Plasticity in Alzheimer's Disease
Teter, B. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:23:3:167 · Cited by 59
“Further, only female E4 transgenic mice (NSE and GFAP) develop agerelated progressive impairments in spatial learning and memory in the water maze and nonspatial novel object recognition memory (Raber et al., 1998, 2000; reviewed in Teter et al., 2002a).”
BackgroundDrouet, B., Fifre, A., Pinçon‐Raymond, M., Vandekerckhove, J. S., Rosseneu, M., Guéant, J., Chambaz, J., & Pillot, T. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00047.x · Cited by 59
“This hypothesis has been partially reinforced by the development of animal models using transgenic mice (Raber et al. 1998; Buttini et al. 1999), but challenged by another study (Holtzman et al. 1999).”
ResultHuang, Y., Driedonks, T. A. P., Cheng, L., Turchinovich, A., Rajapaksha, H., Arab, T., Powell, B. H., Pletniková, O., Redding‐Ochoa, J., Troncoso, J. C., et al. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220322 · Cited by 58
Kaushal, N., Ramesh, V., & Gozal, D. (2012) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00025.2012 · Cited by 55
“Many AD-like features have been reproduced in murine models expressing human ApoE4, including increased plaques (24, 25), reduced presynaptic terminals with ApoE4 (4–6), increased phosphorylated with neuronal expression of ApoE4 (3, 21, 59), and impaired spatial learning and memory (28, 42, 43).”
BackgroundLambert, J., Coyle, N., & Lendon, C. (2004) · Journal of Medical Genetics · doi:10.1136/jmg.2003.005033 · Cited by 51
“78 Experimental and epidemiological findings, although unable to establish a causative effect, are consistent with an accentuated detrimental effect of the e 4 allele in the presence of oestrogen.”
BackgroundPraticò, D., Rokach, J., & Tangirala, R. K. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0730736.x · Cited by 54
“ApoE isoforms have differential effects on mouse brain functions in vivo that are critically influenced by age and gender (Raber et al., 1998).”
BackgroundIntroducing Human APOE into A β Transgenic Mouse Models
Tai, L. M., Youmans, K. L., Jungbauer, L., Yu, C., & LaDu, M. J. (2011) · International Journal of Alzheimer’s Disease · doi:10.4061/2011/810981 · Cited by 52
“Examples include glial fibrillar acidic protein (GFAP; glial) [22, 55–57], transferrin (neuronal) [58], platelet-derived growth factor (PDGF; neuronal) [59], neuron-specific enolase (NSE; neuronal) [15], and thymocyte differentiation antigen 1 (Thy1; neuronal) [59].”
BackgroundMethodInfluentialMa, K., & McLaurin, J. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.5075-13.2014 · Cited by 54
“ApoE4 is a genetic risk factor in AD that induces learning and memory deficits primarily in female mice (Raber et al., 1998).”
BackgroundRao, A. A. N., Ye, H., Decker, P. A., Howe, C. L., & Wetmore, C. (2011) · Journal of Neuro-Oncology · doi:10.1007/s11060-011-0582-9 · Cited by 52
“Behavioral tests were conducted in the order of increasing stress level [ 29 ] on cohorts of 11 mice exposed to fractionated radiation and an equal number of non-irradiated control mice.”
MethodApolipoprotein e ϵ4 and the risk of unfavorable outcome after aneurysmal subarachnoid hemorrhage
Tang, J., Zhao, J., Zhao, Y., Wang, S., Chen, B., & Zeng, W. (2003) · Surgical Neurology · doi:10.1016/s0090-3019(03)00323-9 · Cited by 49
Cambon, K., Davies, H. A., & Stewart, M. G. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00065-8 · Cited by 63
Huang, Y. (2011) · Biochemical Society Transactions · doi:10.1042/bst0390924 · Cited by 53
“, Roses, A.D., Haines, J.L. and Pericak-Vance, M.A. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.”
BackgroundHuman apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice
Ophir, G., Meilin, S., Efrati, M., Chapman, J., Karussis, D., Roses, A. D., & Michaelson, D. M. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(02)00005-0 · Cited by 49
Wang, Z.-H., Xia, Y., Wu, Z., Kang, S. S., Zhang, J.-C., Liu, P., Liu, X., Song, W., Huin, V., Dhaenens, C., et al. (2021) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2021.102212 · Cited by 48
Pontifex, M. G., Vauzour, D., & Minihane, A. M. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.05.017 · Cited by 51
Alzheimer’s disease: the impact of age-related changes in reproductive hormones
Bates, K., Harvey, A. R., Carruthers, M., & Martins, R. N. (2005) · Cellular and Molecular Life Sciences (CMLS) · doi:10.1007/s00018-004-4383-1 · Cited by 47
Rizk‐Jackson, A., Robertson, J., & Raber, J. (2005) · Brain Research · doi:10.1016/j.brainres.2004.12.002 · Cited by 47
Self-citationOng, Q.-R., Chan, E. S., Lim, M.-L., Cole, G. M., & Wong, B.-S. (2014) · Scientific Reports · doi:10.1038/srep03754 · Cited by 44
Androgens, ApoE, and Alzheimer's Disease
Raber, J. (2004) · Science of Aging Knowledge Environment · doi:10.1126/sageke.2004.11.re2 · Cited by 48
Self-citationAdeosun, S. O., Hou, X., Zheng, B., Stockmeier, C. A., Ou, X., Paul, I. A., Mosley, T. H., Weisgraber, K. H., & Wang, J. M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.497909 · Cited by 47
Genetic Mouse Models of Neurodegenerative Diseases
Trancikova, A. K., Ramonet, D., & Moore, D. J. (2011) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-384878-9.00012-1 · Cited by 47
Polis, B., & Samson, A. O. (2024) · Journal of Alzheimer's Disease · doi:10.3233/jad-240058 · Cited by 43
Arf4 Determines Dentate Gyrus-Mediated Pattern Separation by Regulating Dendritic Spine Development
Jain, S., Yoon, S. Y., Zhu, L., Brodbeck, J., Dai, J., Walker, D., & Huang, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046340 · Cited by 43
“These mice have impairments in learning and memory [50], as well as a loss of dendritic spines in primary neurons and in the hippocampus and cortex [21].”
BackgroundRole of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice
Bongers, G., Leurs, R., Robertson, J., & Raber, J. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300352 · Cited by 43
“Young Apoe–/– mice were studied to evaluate a potential role of apoE on H3-receptor-mediated signaling, as adult Apoe –/– mice show age-dependent structural and functional alterations in the cortex and hippocampus (Masliah et al, 1995; Raber et al, 1998; Buttini et al, 1999).”
BackgroundSelf-citationIzco, M., Martinez, P. M., Corrales, A., Fandos, N., García-Cerro, S., Insua, D., Montañés, M., Pérez‐Grijalba, V., Rueda, N., Vidal, V., et al. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.01.003 · Cited by 46
Estrogens, Selective Estrogen Receptor Modulators, and Dementia: What Is the Evidence?
YAFFE, K. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb04024.x · Cited by 43
Age-Related Changes in the Behavior of Apolipoprotein E Knockout Mice
Fuentes, D., Fernández, N., García, Y., García, T. E., Morales, A., & Menéndez, R. (2018) · Behavioral Sciences · doi:10.3390/bs8030033 · Cited by 44
“These discrepancies could be related to environmental factors, compensation by other proteins, genetic background as well as the protocol and behavioral task employed [23,24].”
BackgroundResultSex Differences in Alzheimer’s Disease: Where Do We Stand?
Medeiros, A. D. M., & Silva, R. H. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180213 · Cited by 42
Siegel, J. A., Craytor, M. J., & Raber, J. (2010) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e32833e7e44 · Cited by 43
“Mice lacking apoE show impaired acquisition of a test of attention (Siegel et al., 2009) and mice expressing apoE4 in neurons (Raber et al., 1998) or astrocytes (Van Meer et al., 2007) show impaired spatial learning and memory.”
BackgroundSelf-citationImpairments in spatial memory retention of GFAP-apoE4 female mice
VANMEER, P., Acevedo, S. F., & Raber, J. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.10.024 · Cited by 45
“In contrast, 6-month-old female mice expressing apoE4 in neurons or astrocytes under control of the neuron specific enolase (NSE) or GFAP promoter, respectively, showed impairments in spatial memory retention in the probe trial following three day of hidden platform training in the water maze compared to sex- and age-…”
BackgroundResultInfluentialSelf-citationBrain integrity is altered by hepatic APOE ε4 in humanized-liver mice
Giannisis, A., Patra, K., Edlund, A. K., Nieto, L. A., Benedicto-Gras, J., Moussaud, S., de la Rosa, A., Twohig, D., Bengtsson, T., Fu, Y., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01548-0 · Cited by 40
Self-citationJain, S., Yoon, S. Y., Leung, L., Knöferle, J., & Huang, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059478 · Cited by 39
“We analyzed transgenic mice expressing human apoE3 or apoE4 in CNS neurons under control of a neuron-specific enolase promoter on a mouse apoE-deficient background [15,16,29].”
BackgroundMethodInfluentialRole of circulating androgen levels in effects of apoE4 on cognitive function
Pfankuch, T., Rizk‐Jackson, A., Olsen, R. H. J., Poage, C. T., & Raber, J. (2005) · Brain Research · doi:10.1016/j.brainres.2005.06.028 · Cited by 40
Self-citationVeinbergs, I., Van Uden, E., Mallory, M., Alford, M., McGiffert, C., DeTeresa, R., Orlando, R., & Masliah, E. (2001) · Experimental Neurology · doi:10.1006/exnr.2001.7684 · Cited by 29
Transgenic animal models of neurodegeneration based on human genetic studies
Harvey, B. K., Richie, C. T., Hoffer, B. J., & Airavaara, M. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0476-6 · Cited by 38
“However, replacement of the mouse APOE gene with human APOE4 allele causes cognitive impairments (Raber et al. 1998), decreased excitatory synaptic transmission and reduction in dendritic density and complexity (Wang et al. 2005a; Dumanis et al. 2009), There is also strong evidence that…”
Chan, E. S., Shetty, M. S., Sajikumar, S., Chen, C., Soong, T. W., & Wong, B.-S. (2016) · Scientific Reports · doi:10.1038/srep26119 · Cited by 39
“This is because female ApoE4 mice display greater cognitive impairment than male ApoE4 mice 54–56 .”
ApoE mimetic improves pathology and memory in a model of Alzheimer’s disease
Krishnamurthy, K., Cantillana, V., Wang, H., Sullivan, P. M., Kolls, B. J., Ge, X., Lin, Y., Mace, B., & Laskowitz, D. T. (2020) · Brain Research · doi:10.1016/j.brainres.2020.146685 · Cited by 39
APOEgene and neuropsychiatric disorders and endophenotypes: A comprehensive review
Forero, D. A., López‐León, S., González‐Giraldo, Y., Dries, D. R., Pereira‐Morales, A. J., Jiménez, K. M., & Franco‐Restrepo, J. E. (2016) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32516 · Cited by 38
“…Masliah et al., 1995; Oitzl et al., 1997; Robertson et al., 2005; Siegel et al., 2011; Lane-Donovan et al., 2016; Lee et al., 2016], transgenic [Raber et al., 1998; Hartman et al., 2001; Harris et al., 2003; Levi et al., 2003; Robertson et al., 2005; Korwek et al., 2009; Nichol et al., 2009;…”
BackgroundInfluentialMolecular Pathology of Alzheimer’s Disease and Related Disorders
Ginsberg, S. D., Schmidt, M. L., Crino, P. B., Eberwine, J. H., Lee, V. M. ‐., & Trojanowski, J. Q. (1999) · Cerebral cortex · doi:10.1007/978-1-4615-4885-0_17 · Cited by 38
Montine, T. J., Montine, K. S., Olson, S. J., Graham, D. G., Roberts, L. J., Morrow, J. D., Linton, M. F., Fazio, S., & Swift, L. L. (1999) · Experimental Neurology · doi:10.1006/exnr.1999.7067 · Cited by 37
The presence of apoE4, not the absence of apoE3, contributes to AD pathology
Teter, B., Raber, J., Nathan, B., & Crutcher, K. A. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4305 · Cited by 37
“ApoE4-induced cognitive deficits can be detected even earlier with a modified version of the water maze test, in which the platform location is hidden from the start and changed daily [67].”
Self-citationBehavioral phenotype and BDNF differences related to apoE isoforms and sex in young transgenic mice
Reverte, I., Klein, A. B., Ratner, C., Domingo, J. L., & Colomina, M. T. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.06.015 · Cited by 41
“ApoE4-related cognitive impairments in the Morris Water Maze (MWM) were more evident in females, progressively worsening with age (Bour et al., 2008; Grootendorst et al., 2005; Raber et al., 1998, 2000).”
Education modifies the effect of apolipoprotein epsilon 4 on cognitive decline
Shadlen, M., Larson, E. B., Wang, L., Phelan, E. A., McCormick, W. C., Jolley, L., Teri, L. L., & van Belle, G. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.03.005 · Cited by 36
Unintended Effects of Cranial Irradiation on Cognitive Function
Raber, J. (2009) · Toxicologic Pathology · doi:10.1177/0192623309352003 · Cited by 35
“As female mice are more susceptible than male mice to apoE4induced cognitive impairments (Raber et al. 1998; Raber et al. 2000; Raber et al. 2002), the susceptibility to develop cognitive impairments following cranial irradiation might also be sex dependent.”
BackgroundSelf-citationApoE isoform‐dependent deficits in extinction of contextual fear conditioning
Olsen, R. H. J., Agam, M., Davis, M. J., & Raber, J. (2012) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2012.00833.x · Cited by 35
“In contrast, in mice expressing apoE in either neurons or astrocytes, apoE4 mice do show cognitive impairments compared with to apoE3 mice (Hartman et al. 2001; Raber et al. 1998; van Meer et al. 2003).”
BackgroundSelf-citationThe neurobiology of APOE in schizophrenia and mood disorders
Gibbons, A. S. (2010) · Frontiers in bioscience · doi:10.2741/3729 · Cited by 35
“These impairments were observed in mice that express APOE e4 in neurons (79, 80) or astrocytes (81).”
BackgroundDu, J., Chang, J., Guo, S., Zhang, Q., & Wang, Z. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.07.032 · Cited by 40
Hippocampus-related cognitive impairments in young apoE4 targeted replacement mice
Salomon-Zimri, S., Boehm-Cagan, A., Liraz, O., & Michaelson, D. M. (2013) · Neurodegenerative Diseases · doi:10.1159/000354777 · Cited by 34
Human ApoE ε4 Alters Circadian Rhythm Activity, IL-1β, and GFAP in CRND8 Mice
Graybeal, J. J., Bozzelli, P. L., Graybeal, L. L., Groeber, C. M., McKnight, P. E., Cox, D. N., & Flinn, J. M. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-132009 · Cited by 36
Metadata
- Authors
- Raber, J., Wong, D., Buttini, M., Orth, M., Bellosta, S., Pitas, R. E., Mahley, R. W., & Mucke, L.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-09
- Volume
- 95
- Issue
- 18
- Pages
- 10914-10919
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC27995
- OpenAlex
- W2106067304
- Cited by
- 364
- References
- 41
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 11 · 2023: 8 · 2022: 6 · 2021: 11 · 2020: 15 · 2019: 9 · 2018: 12 · 2017: 8 · 2016: 20 · 2015: 16 · 2014: 15 · 2013: 16 · 2012: 13
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, APOE isoforms, Alzheimer's disease risk, cognitive impairment, learning deficits, sex differences, age-dependent effects, neuron-specific enolase promoter, transgenic mice, brain function, lipid metabolism
- MeSH terms
- Age Factors, Alleles, Animals, Apolipoproteins E, Avoidance Learning, Exploratory Behavior, Female, Humans, Immunohistochemistry, Mice, Transgenic, Neurons, Phosphopyruvate Hydratase, Sex Factors, Mice, Knockout, Maze Learning, Mice
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