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
Open accessAbstract
Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-β (Aβ) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA). CAA is a common cause of brain hemorrhage and is found in most patients with AD. As in AD, the ϵ4 allele of the apolipoprotein E (apoE) gene ( APOE ) is a risk factor for CAA. To determine the effect of human apoE on CAA in vivo , we bred human APOE3 and APOE4 “knock-in” mice to a transgenic mouse model (Tg2576) that develops amyloid plaques as well as CAA. The expression of both human apoE isoforms resulted in a delay in Aβ deposition of several months relative to murine apoE. Tg2576 mice expressing the more fibrillogenic murine apoE develop parenchymal amyloid plaques and CAA by 9 months of age. At 15 months of age, the expression of human apoE4 led to substantial CAA with very few parenchymal plaques, whereas the expression of human apoE3 resulted in almost no CAA or parenchymal plaques. Additionally, young apoE4-expressing mice had an elevated ratio of Aβ 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of Aβ species within different brain compartments. These findings demonstrate that, once Aβ fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of Aβ 40:42 may favor the formation of CAA versus parenchymal plaques.
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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 [13]
The Results section and Figure 4 report greater parenchymal plaque deposition in 15-month-old APPsw mice expressing human apoE4 than in those expressing apoE3. The paper compares human apoE3 and apoE4, but does not test human apoE2, so it cannot establish the full E4 > E3 > E2 ranking. (LLM, conf=0.90)
Experimental — accuracy not yet measuredApoE4 carriers have increased Aβ burden.
“apoE4 carriers have increased A burden (Beffert et al., 1999;Corder et al., 2004;Fryer et al., 2005).”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Fryer et al., 2005
The Discussion reports greater Aβ deposition in cerebral vessels of apoE4-expressing mice than apoE3-expressing mice, supporting increased burden in that model. It also says human APOE4 is associated with more cerebral amyloid angiopathy in patients with AD, but that parenchymal Aβ was independent of APOE genotype. The source therefore does not establish a general increase in Aβ burden among human apoE4 carriers. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn APP transgenic mouse models, murine ApoE is associated with increased amyloid β plaques while ApoE4 is associated with increased CAA.
“In APP transgenic mouse models, murine ApoE is associated with increased amyloid β plaques while ApoE4 is associated with increased CAA [32,33].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [32]
APP/ε4 mice have increased CAA load.
“In accordance to previously published data concerning ε4 allele effect, we found increased CAA load in APP/ε4 mice [25, 44–46].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [44]
Expression of different isoforms of human ApoE in transgenic mice results in different levels of plaque and CAA burden with apoE4 expression enhancing amyloid deposition compared to apoE3 or apoE2.
“This is further complicated by the fact that expression of different isoforms of human ApoE in transgenic mice results in different levels of plaque and CAA burden with apoE4 expression enhancing amyloid deposition compared to apoE3 or apoE2 [3, 21, 40, 59, 86, 178].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [40]
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Self-citationAPOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease
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Untangling Genetic Risk for Alzheimer’s Disease
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Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis
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Self-citationTranscriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease
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APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1
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“Several studies have shown that mice with ApoE3 and ApoE4 have less total ApoE than mice with ApoE2 [23,24,28,40,41].”
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Self-citation
- Authors
- Fryer, J. D., Simmons, K., Parsadanian, M., Bales, K. R., Paul, S. M., Sullivan, P. M., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Eli Lilly (United States) (US)
- Duke University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-03-16
- Volume
- 25
- Issue
- 11
- Pages
- 2803-2810
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725147
- OpenAlex
- W2068394373
- Cited by
- 278
- References
- 49
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 8 · 2023: 11 · 2022: 6 · 2021: 10 · 2020: 10 · 2019: 14 · 2018: 9 · 2017: 21 · 2016: 14 · 2015: 15 · 2014: 23 · 2013: 8 · 2012: 17
- FWCI
- 9.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG05681, AG13956, AG11355)
- National Institute on Aging (R01AG013956, AG 05681, P50AG005681, R37AG013956, AG13956, P01AG011355)
- National Institute of Neurological Disorders and Stroke (NS034467, R37NS034467, R01NS034467)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- APOE ε4, cerebral amyloid angiopathy, Alzheimer's disease, Tg2576 mice, amyloid-beta clearance, cerebrospinal fluid amyloid-beta
- MeSH terms
- Alkenes, Alzheimer Disease, Animals, Apolipoproteins E, Benzoates, Blood Vessels, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Humans, Mice, Inbred C57BL, Mice, Transgenic, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cerebral Amyloid Angiopathy, Mice, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid
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