Human and Murine ApoE Markedly Alters Aβ Metabolism before and after Plaque Formation in a Mouse Model of Alzheimer's Disease

Fagan, Anne M.; Watson, Melanie; Parsadanian, Maia; Bales, Kelly R.; Paul, Steven M.; Holtzman, David M.

doi:10.1006/nbdi.2002.0483

Cited by 290Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Human and Murine ApoE Markedly Alters Aβ Metabolism before and after Plaque Formation in a Mouse Model of Alzheimer's Disease

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Fagan, Anne M., Watson, Melanie, Parsadanian, Maia, Bales, Kelly R., Paul, Steven M., Holtzman, David M.·2002·Neurobiology of Disease

DOI 10.1006/nbdi.2002.0483

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Abstract

The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD), perhaps through effects on amyloid-beta (Abeta) metabolism. Detailed analyses of various Abeta parameters in aging APP(V717F+/-) transgenic mice expressing mouse apoE, no apoE, or human apoE2, apoE3, or apoE4 demonstrate that apoE facilitates, but is not required for, Abeta fibril formation in vivo. Human apoE isoforms markedly delayed Abeta deposition relative to mouse apoE, with apoE2 (and apoE3 to a lesser extent) having a prolonged ability to prevent Abeta from converting into fibrillar forms. Isoform-specific effects of human apoE on Abeta levels and neuritic plaque formation mimicked that observed in AD (E4 > E3 > E2). Importantly, observation of an apoE-dependent decrease in percent soluble Abeta and enrichment of Abeta in membrane microdomains prior to Abeta deposition indicates that apoE influences Abeta metabolism early in the amyloidogenic process and provides a possible novel mechanism by which apoE affects AD pathogenesis.

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Human apoE isoform-dependent differences in amyloid plaque deposition in APP-transgenic mice follow the pattern E4 > E3 > E2.
“we and others have reported human apoE isoform-dependent differences in amyloid plaque deposition in APP-transgenic mice (E4 > E3 > E2) (10-14).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [11]
mAPOE has been shown to have different effects on Aβ plaque metabolism and formation compared to human APOE.
“However, mAPOE has been shown to have different effects on Aβ plaque metabolism and formation compared to human APOE [104, 105].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [104]
The loss in binding is thought to contribute to a decrease in the clearance of Aβ and thus is part of the mechanism for the increased risk of apoE ɛ4 allele carriers to develop AD.
“The loss in binding is thought to contribute to a decrease in the clearance of Aβ and thus is part of the mechanism for the increased risk of apoE ɛ4 allele carriers to develop AD [13–15].”
From Discovery of a Missense Mutation (Q222K) of the APOE Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [13]
In several different Aβ plaque-depositing mice that are genetically engineered to express the human APOE isoforms instead of mouse APOE, APOE4 induces greater Aβ fibrillization and deposition in compact plaques relative to APOE3, whereas APOE2 markedly delays the onset and decreases the extent of Aβ plaque deposition.
“In several different Aβ plaque-depositing mice that are genetically engineered to express the human APOE isoforms instead of mouse APOE (Box 3), APOE4 induces greater Aβ fibrillization and deposition in compact plaques relative to APOE3, whereas APOE2 markedly delays the onset and decreases the extent of Aβ plaque deposition117–120.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [117]
Apoe knockout plaque-depositing mice still exhibit deposition of Aβ plaques, but the plaques are less compact and do not cause the synaptic and cognitive deficits typical of plaque-depositing mice with Apoe intact.
“Apoe knockout plaque-depositing mice highlight the complexity of the APOE–Aβ interaction, as these mice still exhibit deposition of Aβ plaques, but the plaques are less compact and do not cause the synaptic and cognitive deficits typical of plaque-depositing mice with Apoe intact117,119,122.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [117]

The process of APOE binding to TREM2 and promoting plaque compaction likely explains why both Apoe knockout and Trem2 knockout plaque-depositing mice exhibit reduced microglial reactivity against Aβ plaques and their plaques are less compact.
“This process is likely to explain why both Apoe knockout and Trem2 knockout plaque-depositing mice exhibit reduced microglial reactivity against Aβ plaques and their plaques are less compact117,119,122,155.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [117]
APOE4-targeted replacement mice crossed with AD mouse models accelerate plaque formation compared to APOE3-targeted replacement mice.
“APOE4-targeted replacement mice, expressing the human APOE4 allele instead of the mouse Apoe, crossed with different AD mouse models such as PDAPP, APP/ PS1ΔE9 and 5xFAD, accelerated plaque formation compared to APOE3-targeted replacement mice (Bales et al, 2009; Castellano et al, 2011; Fagan et al, 2002; Holtzman et al, 2000a; Rodriguez et al, 2014; Youmans et al, 2012).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Fagan et al, 2002
Experiments suggest the order APOE4 > APOE3 > APOE2 for effects on amyloid deposition.
“In general, experiments suggest the order of APOE4 > APOE3 > APOE2 for effects on amyloid deposition (Fagan et al, 2002; Castellano et al, 2011; Hudry et al, 2013; Zhao et al, 2016)”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Fagan et al, 2002
Human apoE transgenic mice display an isoform-specific pattern of Aβ deposition in the hippocampus, with apoE4 mice having increased levels of Aβ deposits and more thioflavine-S positive plaques than apoE3 mice.
“Interestingly, the human apoE transgenic mice display an isoform-specific pattern of Aβ deposition in the hippocampus, with apoE4 mice having increased levels of Aβ deposits and more thioflavine-S positive plaques than apoE3 mice (Fagan et al., 2002; Holtzman et al., 2000).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Fagan et al., 2002
Expression of human apoE isoform transgenes in PDAPP mice resulted in a marked delay in the deposition of Aβ and formation of neuritic plaques, compared to PDAPP mice expressing murine apoE or no apoE.
“The expression of human apoE isoform transgenes in PDAPP mice resulted in a marked delay in the deposition of Aβ and formation of neuritic plaques, compared to PDAPP mice expressing murine apoE or no apoE (Fagan et al., 2002; Holtzman et al., 2000; Holtzman et al., 1999).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Fagan et al., 2002
In young PDAPP mice prior to the onset of Aβ deposition, the lack of apoE may actually increase soluble Aβ levels.
“Interestingly, it has been shown that in young PDAPP mice prior to the onset of Aβ deposition, that the lack of apoE may actually increases soluble Aβ levels, a finding that is consistent with cell culture data (Dodart et al., 2002; Fagan et al., 2002).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Fagan et al., 2002
In the PDAPP mouse model, the anatomical pattern of Aβ deposition was markedly different in the absence of apoE.
“Furthermore, in the PDAPP mouse model, the anatomical pattern of Aβ deposition was markedly different (Fagan et al., 2002; Irizarry et al., 2000).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Fagan et al., 2002
ApoE affects amyloid-β deposition in a dosage and isoform-specific fashion (ApoE4>ApoE3>ApoE2).
“To date, substantial evidence has demonstrated ApoE affects amyloid-β deposition in a dosage and isoform-specific fashion (ApoE4>ApoE3>ApoE2)96–100”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [99]
ApoE4 exacerbates the deposition of amyloid plaques in the brain compared to other ApoE isoforms.
“Compared with other ApoE isoforms, ApoE4 exacerbates the deposition of amyloid plaques in the brain98–100.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [99]

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Amyloid β Protein (Aβ) Starts to Deposit As Plasma Membrane-Bound Form in Diffuse Plaques of Brains from Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type, Alzheimer Disease and Nondemented Aged Subjects
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Apolipoprotein E isoform-specific reduction of extracellular amyloid in neuronal cultures
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Human apolipoprotein E4 accelerates β‐amyloid deposition in APPsw transgenic mouse brain
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Astrocytes down‐regulate neuronal β‐amyloid precursor protein expression and modify its processing in an apolipoprotein E isoform‐specific manner
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Price (1999) · doi:10.1002/1531-8249(199903)45:3
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Cole (2000) · doi:10.1002/1097-0029(20000815)50:4

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Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development
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Alzheimer’s Disease: The Challenge of the Second Century
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Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
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Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
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“Consistent with this observation, we found that old PDAPP/TRE mice developed Aβ/amyloid deposition in an apoE isoform-dependent pattern, that is, E4> E3> E2, a finding that extends previous reports of apoE isoform-dependent Aβ deposition in various mouse models (10, 11, 13, 14).”
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Deciphering the Molecular Basis of Memory Failure in Alzheimer's Disease
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Apolipoprotein E in Alzheimer’s disease and other neurological disorders
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APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging
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Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
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apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
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History and progress of hypotheses and clinical trials for Alzheimer’s disease
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Three dimensions of the amyloid hypothesis: time, space and 'wingmen'
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A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model
Lim, G. P., Calon, F., Morihara, T., Yang, F., Teter, B., Ubeda, O. J., Salem, N., Frautschy, S. A., & Cole, G. M. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4225-04.2005 · Cited by 687 · see citing works
ApoE genotype accounts for the vast majority of AD risk and AD pathology
Raber, J., Huang, Y., & Ashford, J. W. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.12.023 · Cited by 599 · see citing works
Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
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Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides
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Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
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Alzheimer's disease as homeostatic responses to age-related myelin breakdown
Bartzokis, G. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.08.007 · Cited by 546 · see citing works
Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis
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Lipids and Alzheimer’s Disease
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Karch, C. M., Cruchaga, C., & Goate, A. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.041 · Cited by 473 · see citing works
ApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition
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Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease
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Accelerating Amyloid-β Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models
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Targeted nanoparticles for drug delivery through the blood–brain barrier for Alzheimer's disease
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Deficiency of ABCA1 Impairs Apolipoprotein E Metabolism in Brain
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Astrocyte phenotype in relation to Alzheimer‐type pathology in the ageing brain
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Dimeric Amyloid β Protein Rapidly Accumulates in Lipid Rafts followed by Apolipoprotein E and Phosphorylated Tau Accumulation in the Tg2576 Mouse Model of Alzheimer's Disease
Kawarabayashi, T., Shoji, M., Younkin, L. H., Lin, W.-L., Dickson, D. W., Murakami, T., Matsubara, E., Abe, K., Ashe, K. H., & Younkin, S. G. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.5543-03.2004 · Cited by 365 · see citing works
IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior
Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J. A., Funk, C. C., Moore, B., DiNunno, N., Rosario, A. M., Cruz, P. E., Verbeeck, C., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.11.020 · Cited by 354 · see citing works
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deußing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019) · doi:10.7892/boris.125653 · Cited by 352 · see citing works
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Transgenic mouse models of Alzheimer’s disease.
Elder, G. A., Gama Sosa, M. A., & De Gasperi, R. (2010) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20159 · Cited by 336 · see citing works
Neurogenesis and Alzheimer's disease: At the crossroads
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Deletion of Abca1 Increases Aβ Deposition in the PDAPP Transgenic Mouse Model of Alzheimer Disease
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Solving neurodegeneration: common mechanisms and strategies for new treatments
Wareham, L. K., Liddelow, S. A., Temple, S., Benowitz, L. I., Di Polo, A., Wellington, C., Goldberg, J. L., He, Z., Duan, X., Bu, G., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00524-0 · Cited by 324 · see citing works
Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide
Hashimoto, T., Serrano-Pozo, A., Hori, Y., Adams, K. W., Takeda, S., Banerji, A. O., Mitani, A., Joyner, D., Thyssen, D. H., Bacskai, B. J., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1542-12.2012 · Cited by 294 · see citing works
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Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities
Hemonnot, A.-L., Hua, J., Ulmann, L., & Hirbec, H. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00233 · Cited by 298 · see citing works
Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis
Chen, Y., Strickland, M. R., Soranno, A., & Holtzman, D. M. (2021) · Neuron · doi:10.1016/j.neuron.2020.10.008 · Cited by 298 · see citing works
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ApoE facilitates the microglial response to amyloid plaque pathology
Ulrich, J. D., Ulland, T. K., Mahan, T. E., Nyström, S., Nilsson, K. P., Song, W. M., Zhou, Y., Reinartz, M., Choi, S., Jiang, H., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20171265 · Cited by 297 · see citing works
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APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
Human Apolipoprotein E4 Alters the Amyloid-β 40:42 Ratio and Promotes the Formation of Cerebral Amyloid Angiopathy in an Amyloid Precursor Protein Transgenic Model
Fryer, J. D., Simmons, K., Parsadanian, M., Bales, K. R., Paul, S. M., Sullivan, P. M., & Holtzman, D. M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.5170-04.2005 · Cited by 278 · see citing works
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Apolipoprotein E Regulates the Integrity of Tight Junctions in an Isoform-dependent Manner in an in Vitro Blood-Brain Barrier Model
Nishitsuji, K., Hosono, T., Nakamura, T., Bu, G., & Michikawa, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.225532 · Cited by 275 · see citing works
HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice
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The Blood Brain Barrier in Neurodegenerative Disease: A Rhetorical Perspective
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The LXR agonist TO901317 selectively lowers hippocampal Aβ42 and improves memory in the Tg2576 mouse model of Alzheimer's disease
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APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease
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The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease
Hirsch-Reinshagen, V., Maia, L. F., Burgess, B. L., Blain, J.-F., Naus, K. E., McIsaac, S. A., Parkinson, P. F., Chan, J. Y., Tansley, G. H., Hayden, M. R., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508781200 · Cited by 233 · see citing works
Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype
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Cholesterol homeostasis in neurons and glial cells
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Cell type‐specific roles of APOE4 in Alzheimer disease
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Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins
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Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease
Dodart, J.-C., Marr, R. A., Koistinaho, M., Gregersen, B. M., Malkani, S., Verma, I. M., & Paul, S. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409072102 · Cited by 207 · see citing works
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Regulation of amyloid-β dynamics and pathology by the circadian clock
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Amyloid-β and Tau at the Crossroads of Alzheimer’s Disease
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Apolipoproteins in the brain: implications for neurological and psychiatric disorders
Elliott, D. A., Weickert, C. S., & Garner, B. (2010) · Clinical Lipidology · doi:10.2217/clp.10.37 · Cited by 196 · see citing works
Multifaceted roles of APOE in Alzheimer disease
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Gene Transfer of Human Apoe Isoforms Results in Differential Modulation of Amyloid Deposition and Neurotoxicity in Mouse Brain
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Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease
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The forgotten APOE allele: A review of the evidence and suggested mechanisms for the protective effect of APOE ɛ2
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Formation and function of apolipoprotein E-containing lipoproteins in the nervous system
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APOE genotype regulates pathology and disease progression in synucleinopathy
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Transgenic mouse models of alzheimer disease: Developing a better model as a tool for therapeutic interventions.
Kitazawa, M., Medeiros, R., & M. LaFerla, F. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212799315786 · Cited by 178 · see citing works
Circadian and sleep dysfunction in Alzheimer’s disease
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PET amyloid-beta imaging in preclinical Alzheimer's disease
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Reducing Human Apolipoprotein E Levels Attenuates Age-Dependent Aβ Accumulation in Mutant Human Amyloid Precursor Protein Transgenic Mice
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Mechanism of Cerebral β-Amyloid Angiopathy: Murine and Cellular Models
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Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice
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Apolipoprotein E Markedly Facilitates Age-Dependent Cerebral Amyloid Angiopathy and Spontaneous Hemorrhage in Amyloid Precursor Protein Transgenic Mice
Fryer, J. D., Taylor, J. W., DeMattos, R. B., Bales, K. R., Paul, S. M., Parsadanian, M., & Holtzman, D. M. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-21-07889.2003 · Cited by 160 · see citing works
Self-citation
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Authors: Fagan, A. M., Watson, M., Parsadanian, M., Bales, K. R., Paul, S. M., & Holtzman, D. M.
Affiliations: Washington University in St. Louis (US)
Eli Lilly (United States) (US)
ORCID: Fagan, Anne M.
Paul, Steven M.
Holtzman, David M.
Venue: Neurobiology of Disease
Publisher: Elsevier BV
Published: 2002-04
Volume: 9
Issue: 3
Pages: 305-318
ISSN: 0969-9961 (ISSN-L)
DOI: 10.1006/nbdi.2002.0483
OpenAlex: W1991607389
Cited by: 290
References: 69
Citations by year: 2026: 4 · 2025: 15 · 2024: 22 · 2023: 4 · 2022: 15 · 2021: 7 · 2020: 15 · 2019: 14 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 9 · 2014: 8 · 2013: 6 · 2012: 13
FWCI: 10.81
Type: journal article
Language: en
Open access: green
doaj.org
Licence: cc-by-sa
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neurobiology of Disease (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institute on Aging (AG11355, AG00861-01, AG05681-16, P50AG005681, AG13956, P01AG011355)
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, Alzheimer's disease, amyloid-beta metabolism, APOE ε4, APOE isoforms, APP transgenic mice, neuritic plaques, soluble amyloid-beta, lipid rafts, APOE2, APOE3
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Hippocampus, Humans, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Protein Isoforms, Mice, Plaque, Amyloid

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Human and Murine ApoE Markedly Alters Aβ Metabolism before and after Plaque Formation in a Mouse Model of Alzheimer's Disease

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