The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
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
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Cited by
Sorted by citations
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836
Self-citationAlzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758
Self-citationThe role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
“Following these initial studies with apoE knockout mice, several lines of transgenic mice were generated to study the role of human apoE isoforms in AD pathogenesis (Raber et al., 1998; Sun et al., 1998; Xu et al., 1996).”
Sex modifies the APOE ‐related risk of developing Alzheimer disease
Altmann, A., Tian, L., Henderson, V. W., Greicius, M. D., & Alzheimer's Disease Neuroimaging Initiative Investigators (2014) · Annals of Neurology · doi:10.1002/ana.24135 · Cited by 891
“Explicitly modeling this interaction, both in human studies and animal model studies, as is now only occasionally done, has the potential to yield new insights into the strongest genetic risk factor for late-onset AD 30–32 .”
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600549103 · Cited by 912
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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