ole of apoE/Aβ Interactions in the Pathogenesis of Alzheimer's Disease and Cerebral Amyloid Angiopathy
Abstract
The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The mechanism underlying this increased risk is not completely clear, yet mounting evidence supports the idea that the ability of apoE to interact with the amyloid-beta (Abeta) peptide and influence its conformation and clearance plays a major role. Evidence to support this concept comes from in vitro and in vivo studies of apoE/Abeta interactions and the effects of these interactions on Abeta conformation and cellular clearance. Recent studies on the effect of murine and human apoE in APP transgenic mice provide direct evidence that apoE is critically involved in the in vivo converstion of Abeta into forms which contain high 5-sheet content and associated cellular toxicity (neuritic plaques and CAA). These studies also suggest a role for human apoE in Abeta clearance in vivo.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
apoE is synthesized mainly by astrocytes and plays an isoform-dependent role in modulating Aβ fibrillization and clearance.
“apoE is synthesized mainly by astrocytes and plays an isoform-dependent role in modulating Aβ fibrillization and clearance (Holtzman, 2001; Zlokovic et al., 2005; Kim et al., 2009).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Holtzman, 2001
Cites
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920 · see citing works
Ma, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871 · see citing works
Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1197-263 · Cited by 830 · see citing works
Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins
Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., & Mahley, R. W. (1987) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(87)90295-5 · Cited by 693 · see citing works
Sullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H., & Maeda, N. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.17972 · Cited by 575 · see citing works
Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation.
Linton, M. F., Gish, R., Hubl, S. T., Bütler, E., Esquivel, C., Bry, W. I., Boyles, J. K., Wardell, M. R., & Young, S. G. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115288 · Cited by 367 · see citing works
Nascent astrocyte particles differ from lipoproteins in CSF
LaDu, M. J., Gilligan, S. M., Lukens, J. R., Cabana, V. G., Reardon, C. A., Van Eldik, L. J., & Holtzman, D. M. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70052070.x · Cited by 285 · see citing works
Association of apolipoprotein E ϵ2 and vasculopathy in cerebral amyloid angiopathy
Greenberg, S. M., Vonsattel, J.-P. G., Segal, A. Z., Chiu, R. I., Clatworthy, A. E., Liao, A., Hyman, B. T., & Rebeck, G. W. (1998) · Neurology · doi:10.1212/wnl.50.4.961 · Cited by 267 · cited 1× · see citing works
“In addition, the ε2 allele has been linked to greater risk of CAA-associated vasculopathy and central nervous system (CNS) hemorrhage (Nicoll et al., 1997; Greenberg et al., 1998).”
BackgroundApolipoprotein E and cognitive performance
Raber, J., Wong, D., Yu, G.-Q., Buttini, M., Mahley, R. W., Pitas, R. E., & Mucke, L. (2000) · Nature · doi:10.1038/35006165 · Cited by 237 · see citing works
Fagan, A. M., Holtzman, D. M., Munson, G., Mathur, T., Schneider, D., Chang, L. K., Getz, G. S., Reardon, C. A., Lukens, J., Shah, J. A., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30001 · Cited by 222 · see citing works
Self-citationGhersi‐Egea, J. ‐., Gorevic, P. D., Ghiso, J., Frangione, B., Patlak, C. S., & Fenstermacher, J. D. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.67020880.x · Cited by 222 · see citing works
Is Alzheimer's disease an apolipoprotein E amyloidosis?
Wisniewski, T., Lalowski, M., Golabek, A., Frangione, B., & Vogel, T. (1995) · The Lancet · doi:10.1016/s0140-6736(95)90701-7 · Cited by 155 · see citing works
Biere, A. L., Ostaszewski, B., Zhao, H., Gillespie, S., Younkin, S. G., & Selkoe, D. J. (1995) · Neurobiology of Disease · doi:10.1006/nbdi.1995.0019 · Cited by 52 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development
Chen, G.-F., Xu, T.-H., Yan, Y., Zhou, Y.-R., Jiang, Y., Melcher, K., & Xu, H. E. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.28 · Cited by 1,965 · see citing works
Masters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.56 · Cited by 1,853 · see citing works
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · see citing works
Self-citationApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition
DeMattos, R. B., Cirrito, J. R., Parsadanian, M., May, P. C., O'Dell, M. A., Taylor, J. W., Harmony, J. A. K., Aronow, B. J., Bales, K. R., Paul, S. M., et al. (2004) · Neuron · doi:10.1016/s0896-6273(03)00850-x · Cited by 459 · see citing works
Self-citationMandrekar-Colucci, S., Karlo, J. C., & Landreth, G. E. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5268-11.2012 · Cited by 355 · see citing works
“…al., 1993; Roses, 1996). apoE is synthesized mainly by astrocytes and plays an isoform-dependent role in modulating A fibrillization and clearance (Holtzman, 2001; Zlokovic et al., 2005; Kim et al., 2009). apoE scaffolds the formation of high-density lipoproteins (HDLs), which traffic cholesterol…”
BackgroundLing, Y., Morgan, K., & Kalsheker, N. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(03)00133-x · Cited by 224 · see citing works
Suri, S., Heise, V., Trachtenberg, A. J., & Mackay, C. E. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.10.010 · Cited by 183 · see citing works
Hartman, R. E., Laurer, H., Longhi, L., Bales, K. R., Paul, S. M., McIntosh, T. K., & Holtzman, D. M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-23-10083.2002 · Cited by 115 · see citing works
Self-citationMaternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes
Mosconi, L., Berti, V., Swerdlow, R. H., Pupi, A., Duara, R., & de Leon, M. (2010) · Human Genomics · doi:10.1186/1479-7364-4-3-170 · Cited by 85 · see citing works
A review of the mechanisms underlying selected comorbidities in Alzheimer’s disease
Maciejewska, K., Czarnecka, K., & Szymański, P. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00293-5 · Cited by 64 · see citing works
Campos-Peña, V., Toral-Rios, D., Becerril-Pérez, F., Sánchez-Torres, C., Delgado-Namorado, Y., Torres-Ossorio, E., Franco-Bocanegra, D., & Carvajal, K. (2017) · Antioxidants & Redox Signaling · doi:10.1089/ars.2016.6768 · Cited by 58 · see citing works
Hurtado, M. O., Kohler, I., & de Lange, E. C. M. (2018) · Bioanalysis · doi:10.4155/bio-2018-0135 · Cited by 34 · see citing works
Ou-Yang, M.-H., & Van Nostrand, W. E. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-134 · Cited by 30 · see citing works
Role of Ion Channels in Alzheimer’s Disease Pathophysiology
Bhoi, R., Mitra, T., Tejaswi, K., Manoj, V., & Ghatak, S. (2025) · The Journal of Membrane Biology · doi:10.1007/s00232-025-00341-8 · Cited by 19 · see citing works
- Authors
- Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Holtzman, David M.
- Venue
- Journal of Molecular Neuroscience
- Published
- 2001
- Volume
- 17
- Issue
- 2
- Pages
- 147-155
- ISSN
- 0895-8696 (ISSN-L)
- OpenAlex
- W2004324219
- Cited by
- 143
- References
- 13
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 10 · 2020: 9 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 2 · 2015: 7 · 2014: 7 · 2013: 11 · 2012: 4
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Chinese Academy of Agricultural Sciences
- National Institutes of Health
- National Institute on Aging (AG11355, AG 05681, 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, APOE ε4, amyloid-beta, Alzheimer's disease, cerebral amyloid angiopathy, amyloid-beta clearance, APP transgenic mice, neuritic plaques, amyloid-beta oligomerization
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Humans, Mice, Transgenic, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Protein Structure, Secondary, Molecular Chaperones, Genetic Predisposition to Disease, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
