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Cited by 364Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: Increased susceptibility of females

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Raber, Jacob, Wong, Derek, Buttini, Manuel, Orth, Matthias, Bellosta, Stefano, Pitas, Robert E., Mahley, Robert W., Mucke, Lennart·1998·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.95.18.10914PMC PMC27995
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Abstract

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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  • APOE4 was previously shown to accelerate AD progression in humans and in mouse models.

    “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]

  • The APOE4 allele is a major genetic risk factor for late-onset Alzheimer's disease.

    “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]

  • Previous attempts to model the effect of apoE4[L28P] in experimental animals have yielded conflicting results.

    “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]

  • Transgenic wild-type apoE4 mice lacking endogenous mouse apoE and expressing human apoE transgenes in neurons under 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.

    “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]

  • Compared with apoE3 transgenic mice, apoE4 transgenic mice were more severely impaired in learning and memory.

    “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

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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)
ORCID
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
DOI
10.1073/pnas.95.18.10914
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
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
  • Health Sciences › Medicine › Physiology › 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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