Apolipoprotein E Markedly Facilitates Age-Dependent Cerebral Amyloid Angiopathy and Spontaneous Hemorrhage in Amyloid Precursor Protein Transgenic Mice
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Cerebral amyloid angiopathy (CAA) is a common cause of brain hemorrhage in the elderly. It is found in the majority of patients with Alzheimer's disease (AD). The most common form of CAA is characterized by the deposition of the amyloid-β (Aβ) peptide in the walls of cerebral vessels, and this deposition can lead to hemorrhage and infarction. As in AD, the ϵ4 allele of apolipoprotein E (APOE) is a risk factor for CAA. To determine the effect of apoE on CAA and associated hemorrhage in vivo, we used two amyloid precursor protein (APP) transgenic mouse models that develop age-dependent Aβ deposition: PDAPP and APPsw mice. We found that both models developed an age-dependent increase in CAA and associated microhemorrhage, with the APPsw model having an earlier and more severe phenotype; however, when APPsw and PDAPP mice were bred onto an Apoe-/- background, no CAA was detected through 24 months of age, and there was little to no evidence of microhemorrhage. Biochemical analysis of isolated cerebral vessels from both PDAPP and APPsw mice with CAA revealed that, as in human CAA, the ratio of Aβ 40:42 was elevated relative to brain parenchyma. In contrast, the ratio of Aβ 40:42 from cerebral vessels isolated from old PDAPP,Apoe-/- mice was extremely low. These findings demonstrate that murine apoE markedly promotes the formation of CAA and associated vessel damage and that the effect of apoE combined with the level of Aβ 40 or the ratio of Aβ 40:42 facilitates this process.
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In several AD Tg mouse models, lack of apoE is associated with absence of fibrillar Aβ deposits and prevented neurodegeneration.
“Our findings remain consistent with the effects of apoE knock-out noted in several AD Tg mouse models, where lack of apoE was associated with absence of fibrillar Aβ deposits and prevented neurodegeneration [13,29,31,32].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [32]
The Results and Discussion report that apoE knockout prevented cerebral vascular amyloid in the APPsw and PDAPP mouse models. They also state that fibrillar Aβ deposits appeared in the brain parenchyma of older knockout mice, so the claimed absence of fibrillar deposits is too broad. The paper reports reduced microhemorrhages, not prevention of neurodegeneration; page numbers were not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPP/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 [25]
The Results and Figure 3 report higher CAA load in APP transgenic mice with murine apoE than in mice lacking apoE. They do not establish an effect of the human ε4 allele in APP/ε4 mice; the Discussion says whether different human apoE isoforms have similar effects on CAA is unknown. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoE plays a key role in CAA development.
“Although apoE is known to play a key role in CAA development (Holtzman et al., 2000;Fryer et al., 2003), therapeutic antibodies targeting apoE may induce fewer or no side effects associated with CAA.”
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 Fryer et al., 2003
VAβ is detrimental to the function of cerebrovascular circulation through compromising blood-brain-barrier integrity, effecting hemodynamic dysfunction, and facilitating occurrence of spontaneous hemorrhages.
“VAβ is detrimental to the function of cerebrovascular circulation through compromising blood–brain-barrier integrity [49], effecting hemodynamic dysfunction [29, 50], and facilitating occurrence of spontaneous hemorrhages [25, 26, 36].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [25]
Presence of apoE within CAA lesions is critical for formation of Aβ fibrillar assemblies.
“Presence of apoE within CAA lesions is critical for formation of Aβ fibrillar assemblies [25].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [25]
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 [41]
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References 73 · Cited by 160
- Authors
- Fryer, J. D., Taylor, J. W., DeMattos, R. B., Bales, K. R., Paul, S. M., Parsadanian, M., & Holtzman, D. M.
- Affiliations
- Eli Lilly (United States) (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-08-27
- Volume
- 23
- Issue
- 21
- Pages
- 7889-7896
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740607
- OpenAlex
- W2101985994
- Cited by
- 160
- References
- 73
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 10 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 7 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 12
- FWCI
- 7.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG05681, AG13956, AG11355)
- National Institute on Aging (AG11355, R01AG013956, AG 05681, P50AG005681, R37AG013956, AG13956, P01AG011355)
- National Institute of Neurological Disorders and Stroke (NS034467, R37NS034467, R01NS034467)
- Topics
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- cerebral amyloid angiopathy, apolipoprotein E, amyloid precursor protein transgenic mice, PDAPP mice, microhemorrhages, amyloid-beta deposition, APOE ε4, Alzheimer's disease, apolipoprotein E deficiency
- MeSH terms
- Age Factors, Animals, Apolipoproteins E, Cerebral Cortex, Cerebral Hemorrhage, Mice, Transgenic, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cerebral Amyloid Angiopathy, Mice, Knockout, Mice
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