Apolipoprotein E is essential for amyloid deposition in the APP V717F transgenic mouse model of Alzheimer's disease

Bales, Kelly R.; Verina, Tatyana; Cummins, David J.; Du, Yansheng; Dodel, Richard C.; Saura, Josep; Fishman, Cindy E.; DeLong, Cynthia A.; Piccardo, Pedro; Petegnief, Valerie; Ghetti, Bernardino; Paul, Steven M.

doi:10.1073/pnas.96.26.15233

Cited by 486Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Apolipoprotein E is essential for amyloid deposition in the APP V717F transgenic mouse model of Alzheimer's disease

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Bales, Kelly R., Verina, Tatyana, Cummins, David J., Du, Yansheng, Dodel, Richard C., Saura, Josep, Fishman, Cindy E., DeLong, Cynthia A. +4 more·1999·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.96.26.15233PMC PMC24803

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Abstract

We quantified the amount of amyloid β-peptide (Aβ) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein ( APP V717F+/− TG mice) with no, one, or two mouse apolipoprotein E ( Apoe ) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP V717F+/− Apoe −/− TG mice as old as 22 mo of age, whereas age-matched APP V717F +/− Apoe +/− and Apoe +/+ TG mice display abundant amyloid deposition. The amount of Aβ immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner ( Apoe +/+ > Apoe +/− ≫ Apoe −/− ), and no Aβ immunoreactivity was detected in the cerebral cortex of APP V717F+/− Apoe −/− TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both Aβ 1–40 and Aβ 1–42 immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP V717F TG mice. ApoE immunoreactivity was detected in a subset of Aβ immunoreactive deposits and in virtually all thioflavine-S-fluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP V717F transgene nor its processing to Aβ peptide(s), we postulate that apoE promotes both the deposition and fibrillization of Aβ, ultimately affecting clearance of protease-resistant Aβ/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.

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Absence of apoE leads to a dramatic decrease in the levels of fibrillar Aβ deposits in APP transgenic mouse models.
“Previous studies demonstrated that the absence of apoE leads to a dramatic decrease in the levels of fibrillar Aβ deposits in APP transgenic mouse models (Bales et al., 1999; Bales et al., 1997; Holtzman et al., 2000a; Holtzman et al., 2000b).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Bales et al., 1999
Lack of apoE leads to a dramatic reduction of fibrillar Aβ deposition in APP transgenic mouse models.
“Later, in vivo studies demonstrated that the lack of apoE led to a dramatic reduction of fibrillar Aβ deposition in APP transgenic mouse models (Bales et al., 1999; Bales et al., 1997; Holtzman et al., 2000a; Holtzman et al., 2000b).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Bales et al., 1999
Genetic deletion and pharmacological reduction of APOE reduce Aβ deposition in mouse models of Alzheimer's disease.
“Both genetic deletion and pharmacological reduction of APOE reduced Aβ deposition in mouse models of AD. 3 , 4 , 5 , 6 , 7 , 8 , 9”
From Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [4]
Deletion of Apoe reduces amyloid deposition in transgenic mouse models of AD.
“Notably, deletion of Apoe reduces amyloid deposition in transgenic mouse models of AD. 3 , 4”
From Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [4]
Decreasing the apoE level by haploinsufficiency of apoE results in decreased amyloidosis.
“Conversely, blocking the interaction between apoE and A␤ (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999;Holtzman et al., 2000;Kim et al., 2011;Bien-Ly et al., 2012) results in decreased amyloidosis.”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Bales et al., 1999

In amyloid precursor protein-expressing transgenic mice, deletion of the mouse apoE gene inhibits development of fibrillar amyloid plaques.
“In amyloid precursor proteineexpressing transgenic mice, deletion of mouse apoE gene inhibits development of fibrillar amyloid plaques [80,81].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [81]
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 [118]
APOE has been shown to influence Aβ plaque morphology.
“APOE has been shown to influence Aβ plaque morphology.”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [44]
Apoe knockout mice exhibit markedly reduced amyloid deposition and develop diffuse, amorphous plaques.
“Apoe knockout mice exhibit markedly reduced amyloid deposition and develop diffuse, amorphous plaques. [44–46].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [44]
ApoE-deficient APP transgenic mice display virtually no fibrillar Aβ deposits nor neuritic degeneration.
“apoE-deficient APP transgenic mice display virtually no fibrillar Aβ deposits nor neuritic degeneration”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bales et al 1999
Amyloid deposition in APP transgenic mice occurs in an APOE gene dose-dependent manner, with two copies of human APOE exhibiting more amyloid deposition than one copy.
“amyloid deposition in APP transgenic mice occurs in an APOE gene dose-dependent manner in which mice containing two copies of human APOE gene exhibit more amyloid deposition than those with only one copy”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bales et al 1999
APP transgenic mice lacking endogenous mouse apoE display a significant decrease of amyloid pathology.
“APP transgenic mice lacking endogenous mouse apoE display a significant decrease of amyloid pathology”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bales et al 1999
Astrogliosis and microgliosis typical in mice with amyloidosis are reduced in the absence of apoE.
“astrogliosis and microgliosis, typical in mice with amyloidosis, are also reduced in the absence of apoE”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Bales et al 1999
AD mouse models show limited amyloid plaque pathology in the absence of Apoe.
“AD mouse models show limited amyloid plaque pathology in the absence of Apoe (Bales et al, 1999; Holtzman et al, 2000b; Ulrich et al, 2018).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Bales et al, 1999
Knocking out mouse Apoe leads to a significant reduction of fibrillar plaque formation in different AD mouse models.
“Previous studies have shown that knocking out mouse Apoe leads to a significant reduction of fibrillar plaque formation in different AD mouse models (Bales et al, 1999; Holtzman et al, 2000b; Ulrich et al, 2018).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Bales et al, 1999
Multiple studies suggest that lowering ApoE levels reduces relevant pathology in both amyloidosis and tauopathy mouse models.
“Multiple studies employing ApoE genetic deletion (Bales et al., 1999; Verghese et al., 2013), conditional expression of ApoE isoforms (Liu et al., 2017) or ASO-mediated knockdown of ApoE expression (Huynh et al., 2017b) suggest that lowering ApoE levels reduces relevant pathology in both amyloidosis and tauopathy mouse models (Shi et al., 2017).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Bales et al., 1999
ApoE assists in amyloid-β clearance in an isoform-dependent manner wherein apoE2 > apoE3 > apoE4.
“ApoE assists in Aβ clearance in an isoform-dependent manner wherein apoE2 > apoE3 > apoE4 [29, 30, 59].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [29]
Transgenic mouse studies confirmed that ApoE was necessary for the formation of fibrillar amyloid plaques and CAA.
“Transgenic mouse studies confirmed that ApoE was necessary for the formation of fibrillar amyloid plaques and CAA [4, 5, 41, 61], however they also identified important differences between mouse and human ApoE.”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [4]

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Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis
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Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis
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“…between apoE and A (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999; Holtzman et al., 2000; Kim et al., 2011; Bien-Ly et al., 2012) results in decreased amyloidosis.”
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Homeostatic Microglia Initially Seed and Activated Microglia Later Reshape Amyloid Plaques in Alzheimer's Disease
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Introducing Human APOE into Aβ Transgenic Mouse Models
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“3,4 Because LDLR is a major endocytic APOE receptor, 59 it was hypothesized that modulating LDLR levels could influence brain APOE levels.”
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Authors: Bales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., Fishman, C. E., DeLong, C. A., Piccardo, P., Petegnief, V., Ghetti, B., & Paul, S. M.
Affiliations: Purdue University West Lafayette (US)
Neuroscience Discovery Research and Statistical and Mathematical Sciences, Lilly Research Laboratories, Indianapolis, IN 46285; Departments of Pathology and Laboratory Medicine and Pharmacology, Toxicology, and Psychiatry, Indiana School of Medicine, Indianapolis, IN 46285; Department of Neurology, Phillips University, Marburg, Germany; and Department of Veterinary Pathobiology, Purdue University, West Lafayette, IN 47907
Corresponding author: Paul, Steven M.
ORCID: Du, Yansheng
Dodel, Richard C.
Saura, Josep
Fishman, Cindy E.
Ghetti, Bernardino
Paul, Steven M.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1999-12-21
Volume: 96
Issue: 26
Pages: 15233-15238
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.96.26.15233
PMC: PMC24803
OpenAlex: W2152192643
Cited by: 486
References: 50
Citations by year: 2026: 5 · 2025: 8 · 2024: 15 · 2023: 7 · 2022: 14 · 2021: 9 · 2020: 19 · 2019: 10 · 2018: 11 · 2017: 11 · 2016: 11 · 2015: 11 · 2014: 18 · 2013: 12 · 2012: 20
FWCI: 14.08
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
Funders: Alzheimer's Association
Eli Lilly and Company
National Institute on Aging (P30AG010133)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: apolipoprotein E, amyloid-beta, amyloid deposition, Alzheimer's disease, amyloid fibril formation, astrocyte activation, microglial activation, amyloid clearance, hippocampus, cerebral cortex
MeSH terms: Alzheimer Disease, Amyloid, Animals, Apolipoproteins E, Brain, Cerebral Cortex, Disease Models, Animal, Gliosis, Heterozygote, Hippocampus, Homozygote, Mice, Transgenic, Neuroglia, Amyloid beta-Protein Precursor, Mice, Knockout, Mice

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Apolipoprotein E is essential for amyloid deposition in the APP V717F transgenic mouse model of Alzheimer's disease

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