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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]
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Neuroplasticity in Alzheimer's disease
Teter, B., & Ashford, J. W. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10441 · Cited by 170
“Second, E4specifc cognitive impairments in these same mice (NSE) are not present in nontransgenic apoE-ko littermates (this “gain of function” is in comparison to apoE-ko, not a dose response of E4) (Raber et al., 1998, 2000; reviewed in Teter et al., 2002).”
BackgroundChen, H.-K., Liu, Z., Meyer-Franke, A., Brodbeck, J., Miranda, R. D., McGuire, J. G., Pleiss, M. A., Ji, Z.-S., Balestra, M. E., Walker, D. W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.276162 · Cited by 163
Self-citationLaws, S. M., Hone, E., Gandy, S., & Martins, R. N. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01615.x · Cited by 223
Clinical correlates in an experimental model of repetitive mild brain injury
Mannix, R., Meehan, W. P., III, Mandeville, J. B., Grant, P. E., Gray, T., Berglass, J., Zhang, J., Bryant, J., Rezaie, S., Chung, J. Y., et al. (2013) · Annals of Neurology · doi:10.1002/ana.23858 · Cited by 160
Hartman, R. E., Wozniak, D. F., Nardi, A., Olney, J. W., Sartorius, L., & Holtzman, D. M. (2001) · Experimental Neurology · doi:10.1006/exnr.2001.7715 · Cited by 157
Mayeux, R. P., Small, S. A., Tang, M., Tycko, B., & Stern, Y. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00223-8 · Cited by 156
“Compared with intact mice, APOE deficient mice have decreased synaptic density in cholinergic, noradrenergic and serotinergic projections to relevant brain regions [13] and perform worse in several types of memory tasks [8,16,42,43].”
BackgroundAD-linked R47H- TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation
Sayed, F. A., Kodama, L., Fan, L., Carling, G. K., Udeochu, J. C., Le, D., Li, Q., Zhou, L., Wong, M. Y., Horowitz, R., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe3947 · Cited by 155
“APOE4 increases risk for late-onset sporadic AD to a greater extent in females (52, 53), and female APOE4 knock-in mice have spatial memory deficits not seen in males (54).”
BackgroundHarris, F. M., Brecht, W. J., Xu, Q., Mahley, R. W., & Huang, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408127200 · Cited by 151
Self-citationApoE Deficiency Compromises the Blood Brain Barrier Especially After Injury
Methia, N., André, P., Hafezi-Moghadam, A., Economopoulos, M., Thomas, K. L., & Wagner, D. D. (2001) · Molecular Medicine · doi:10.1007/bf03401973 · Cited by 150
Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease
Wadhwani, A. R., Affaneh, A., Van Gulden, S., & Kessler, J. A. (2019) · Annals of Neurology · doi:10.1002/ana.25455 · Cited by 142
Kim, J., Yoon, H., Basak, J., & Kim, J. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0248 · Cited by 141
“…NSE Impairment of WM task and vertical exploratory behavior in apoE4 TG compared to WT and apoE3 TG 5-6 More susceptible in female and aged mice (Raber et al., 1998) Human apoE3,E4 TG crossed with human APP NSE ApoE3 TG is less susceptible to the detrimental effect of APP/A on WM performance…”
BackgroundTesseur, I. C., Dorpe, J. V., Bruynseels, K., Bronfman, F. C., Sciot, R., Lommel, A. V., & LEUVEN, F. V. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64788-8 · Cited by 140
“Effects on learning and exploratory behavior were demonstrated in female NSE-ApoE4 transgenic mice at the age of 6 months, but no axonopathy was reported.(63) In the PDGFApoE4 transgenic mice, we observed a similar, but less severe phenotype as in the Thy1-ApoE4 transgenic mice, but only when they aged to ;2 years.”
BackgroundAPOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction
Soto, I., Graham, L. C., Richter, H. J., Simeone, S. N., Radell, J. E., Grabowska, W., Funkhouser, W. K., Howell, M. C., & Howell, G. R. (2015) · PLOS Biology · doi:10.1371/journal.pbio.1002279 · Cited by 140
Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells
Harris, F. M., Tesseur, I., Brecht, W. J., Xu, Q., Mullendorff, K., Chang, S., Wyss-Coray, T., Mahley, R. W., & Huang, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309475200 · Cited by 135
Self-citationHuman apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology.
Wang, C., Wilson, W. A., Moore, S. D., Mace, B. E., Maeda, N., Schmechel, D. E., & Sullivan, P. M. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.10.013 · Cited by 138
Mahley, R. W., & Huang, Y. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3008618 · Cited by 132
Self-citationGenes contributing to prion pathogenesis
Tamgüney, G., Giles, K., Glidden, D. V., Lessard, P., Wille, H., Tremblay, P., Groth, D., Yehiely, F., Korth, C., Moore, R. C., et al. (2008) · Journal of General Virology · doi:10.1099/vir.0.2008/001255-0 · Cited by 131
“Tg(APOE3) and Tg(APOE4) mice, originally named Tg(NSEapoE3) and Tg(NSE-apoE4), express the e3 or the e4 allele of human apolipoprotein E (APOE) driven by the neuron-specific enolase (NSE) promoter on a C57BL/6J-Apoe (C57BL/6J-Apoe) background (Raber et al., 1998).”
BackgroundSelf-citationRaber, J., Akana, S. F., Bhatnagar, S., Dallman, M. F., Wong, D. T., & Mucke, L. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-05-02064.2000 · Cited by 131
Self-citationGrootendorst, J., Bour, A., Vogel, E., Kelche, C., Sullivan, P. M., Dodart, J.-C., Bales, K., & Mathis, C. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.09.019 · Cited by 148
Bour, A., Grootendorst, J., Vogel, E., Kelche, C., Dodart, J.-C., Bales, K., Moreau, P.-H., Sullivan, P. M., & Mathis, C. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.05.008 · Cited by 141
“Interestingly, conventionally derived transgenic female apoE mice which overexpress apoE4 also exhibit spatial memory deficits [7,24].”
InfluentialThe apolipoprotein E gene, attention, and brain function.
Parasuraman, R., Greenwood, P. M., & Sunderland, T. (2002) · Neuropsychology · doi:10.1037//0894-4105.16.2.254 · Cited by 134
“Raber et al. (1998) used a neuronspecific enolase promoter to express human 3 and 4 ApoE isoforms in ApoE knockout mice.”
MethodReactivity of Apolipoprotein E4 and Amyloid β Peptide
Ji, Z.-S., Müllendorff, K., Cheng, I. H., Miranda, R. D., Huang, Y., & Mahley, R. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m506646200 · Cited by 127
Intron-3 Retention/Splicing Controls Neuronal Expression of Apolipoprotein E in the CNS
Xu, Q., Walker, D., Bernardo, A., Brodbeck, J., Balestra, M. E., & Huang, Y. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3253-07.2008 · Cited by 122
“…function, tau phosphorylation, lysosomal leakage, neurodegeneration, androgen receptor deficiency, and cognitive decline (Tolar et al., 1997, 1999; Raber et al., 1998, 2002; Buttini et al., 1999, 2002; Tesseur et al., 2000; Huang et al., 2001; Ji et al., 2002; Harris et al., 2003, 2004a; Brecht…”
BackgroundSex difference in pathology and memory decline in rTg4510 mouse model of tauopathy
Yue, M., Hanna, A., Wilson, J., Roder, H. M., & Janus, C. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.04.006 · Cited by 125
The amyloid cascade and Alzheimer's disease therapeutics: theory versus observation
Castellani, R. J., Plascencia‐Villa, G., & Perry, G. L. (2019) · Laboratory Investigation · doi:10.1038/s41374-019-0231-z · Cited by 130
Lane-Donovan, C., Wong, W. M., Durakoglugil, M. S., Wasser, C. R., Jiang, S., Xian, X., & Herz, J. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1054-16.2016 · Cited by 115
“It has been shown that female ApoE KO mice display greater cognitive impairment than male ApoE KO mice (Raber et al., 1998), a result we have replicated here.”
BackgroundMarked regional differences of brain human apolipoprotein e expression in targeted replacement mice
Sullivan, P. M., Mace, B. E., Maeda, N., & Schmechel, D. E. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.10.011 · Cited by 113
ApoE and Neurodegenerative Diseases in Aging
Yin, Y., & Wang, Z. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1117-8_5 · Cited by 111
Leung, L., Andrews-Zwilling, Y., Yoon, S. Y., Jain, S., Ring, K., Dai, J., Wang, M. M., Tong, L., Walker, D., & Huang, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0053569 · Cited by 109
“5 cm from the surface during the hidden platform sessions [20,42] and marked with a black-and-whitestriped mast (15 cm high) during the cued training sessions.”
BackgroundJohnson, L. A., Olsen, R. H. J., Merkens, L. S., DeBarber, A., Steiner, R. D., Sullivan, P. M., Maeda, N., & Raber, J. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.12.016 · Cited by 107
Self-citationCathepsin B Degrades Amyloid-β in Mice Expressing Wild-type Human Amyloid Precursor Protein
Wang, C., Sun, B., Zhou, Y., GRUBB, A. O., & Gan, L. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.371641 · Cited by 112
“The PCR fragment was inserted into the NSE vector (15) with blunted HindIII linkers to generate the NSECatB plasmid.”
MethodApolipoprotein E and Alzheimer disease
Huang, Y. (2006) · Neurology · doi:10.1212/01.wnl.0000192102.41141.9e · Cited by 105
Ponsford, J., McLaren, A., Schönberger, M., Burke, R., Rudzki, D., Olver, J., & Ponsford, M. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2010.1623 · Cited by 103
Sabo, T., Lomnitski, L., Nyska, A., Beni, S., Maronpot, R. R., Shohami, E., Roses, A. D., & Michaelson, D. M. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00438-3 · Cited by 104
Anxiety and cognition in histamine H3 receptor−/− mice
Rizk‐Jackson, A., Curley, J., Robertson, J., & Raber, J. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03251.x · Cited by 102
Self-citationPremorbid effects of APOE on synaptic proteins in human temporal neocortex
Love, S., Siew, L. K., Dawbarn, D., Wilcock, G. K., Ben‐Shlomo, Y., & Allen, S. J. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.04.008 · Cited by 101
Mouse behavioural analysis in systems biology
van Meer, P., & Raber, J. (2005) · Biochemical Journal · doi:10.1042/bj20042023 · Cited by 107
Self-citationApolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice
Knoferle, J., Yoon, S. Y., Walker, D., Leung, L., Gillespie, A. K., Tong, L. M., Bien-Ly, N., & Huang, Y. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.2281-14.2014 · Cited by 97
“On the other hand, transgenic mice that express apoE4 under a neuronspecific enolase (NSE) promoter on a mouse apoe knock-out background had earlier and more severe deficits in spatial memory tasks (Raber et al., 1998).”
BackgroundMethodInfluentialButtini, M., Akeefe, H., Lin, C. J., Mahley, R. W., Pitas, R. E., Wyss‐Coray, T., & Mucke, L. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00069-5 · Cited by 98
Self-citation
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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