Novel Role for Apolipoprotein E in the Central Nervous System
Open accessAbstract
It has long been postulated that apolipoprotein E (apoE) may play a role in lipid metabolism in the brain. However, direct evidence that apoE plays such a role is lacking. We investigated whether apoE isoforms influence lipid content in the brain. We compared the brains of wild-type mice to apoE knockout (-/-) and human apoE3 and apoE4 transgenic mice and compared cerebrospinal fluid (CSF) of humans with different apoE isoforms. We found that there was no effect of apoE on the content of multiple phospholipids, sphingolipids, and cholesterol. There was, however, a marked effect of apoE on the sulfatide (ST) content in both the brain and CSF. The sulfatide mass in hippocampus and cortex of apoE knockout mice was found to be 61 and 114 mol% higher than wild-type mice counterparts at 12 months of age. In contrast, the sulfatide content in brain tissues from human apoE4-expressing mice was approximately 60% less than those found in wild-type mice of the same age. The ST mass in human CSF was significantly dependent on the APOE genotypes of the subjects. Examination of potential sulfatide carrier(s) in human CSF demonstrated that sulfatides are specifically associated with apoE-containing high density lipoproteins, suggesting that sulfatide levels in the central nervous system (CNS) are likely to be directly modulated by the same metabolic pathways that regulate levels of apoE-containing CNS lipoproteins. This novel role for apoE in the CNS may provide new insights into the connection of apoE with Alzheimer's disease and poor recovery after brain injury.
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Sulfatide depletion is observed in the early stages of Alzheimer's disease and in amyloid model mice in an age-dependent manner.
“ApoE was shown to regulate the metabolism of sulfatide whose depletion was observed in the early stages of AD and amyloid model mice in an age-dependent manner (41, 42).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [41]
The Abstract reports sulfatide deficiency at the earliest stages of Alzheimer’s disease, and the Results report age-dependent differences in sulfatide levels in apoE transgenic mice. The mice studied for sulfatide levels are not identified as amyloid model mice; the Discussion mentions amyloid models in connection with amyloid deposition, not sulfatide depletion. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoE regulates the metabolism of sulfatide.
“ApoE was shown to regulate the metabolism of sulfatide whose depletion was observed in the early stages of AD and amyloid model mice in an age-dependent manner (41, 42).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [41]
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A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751 · see citing works
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · 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
Han, X., M. Holtzman, D., W. McKeel, D., Kelley, J., & Morris, J. C. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00997.x · Cited by 626 · see citing works
Self-citationFagan, A. M., Watson, M., Parsadanian, M., Bales, K. R., Paul, S. M., & Holtzman, D. M. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0483 · Cited by 290 · see citing works
Self-citationTOKUDA, T., CALERO, M., MATSUBARA, E., VIDAL, R., KUMAR, A., PERMANNE, B., ZLOKOVIC, B., SMITH, J. D., LADU, M. J., ROSTAGNO, A., et al. (2000) · Biochemical Journal · doi:10.1042/bj3480359 · Cited by 272 · see citing works
Sun, Y., Wu, S., Bu, G., Onifade, M. K., Patel, S. N., LaDu, M. J., Fagan, A. M., & Holtzman, D. M. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-09-03261.1998 · Cited by 213 · see citing works
Self-citationDeMattos, R. B., Brendza, R. P., Heuser, J. E., Kierson, M., Cirrito, J. R., Fryer, J., Sullivan, P. M., Fagan, A. M., Han, X., & Holtzman, D. M. (2001) · Neurochemistry International · doi:10.1016/s0197-0186(01)00049-3 · Cited by 180 · see citing works
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Research works printed but not linked: 3
- [1]1. Mahley, R.W. Science. 1988; 240:622-630 Crossref PubMed Google Scholar
- [2]2. Weisgraber, K.H. Adv. Protein Chem. 1994; 45:249-302 Crossref PubMed Google Scholar
- [3]3. Pitas, R.E. ∙ Boyles, J.K. ∙ Lee, S.H. ... J. Biol. Chem. 1987; 262:14352-14360
Cited by
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Cholesterol metabolism in neurons and astrocytes
Pfrieger, F. W., & Ungerer, N. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2011.06.002 · Cited by 500 · see citing works
Liu, Q., Trotter, J., Zhang, J., Peters, M. M., Cheng, H., Bao, J., Han, X., Weeber, E. J., & Bu, G. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4067-10.2010 · Cited by 268 · see citing works
Self-citationHan, X. (2005) · Current Alzheimer Research · doi:10.2174/1567205052772786 · Cited by 183 · see citing works
Self-citation<i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
Liu, C.-C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A.-C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc9375 · Cited by 108 · see citing works
Self-citationAPP Function and Lipids: A Bidirectional Link
Grimm, M. O. W., Mett, J., Grimm, H. S., & Hartmann, T. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00063 · Cited by 104 · see citing works
Lipid metabolism in Alzheimer’s disease
Liu, Q., & Zhang, J. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-013-1410-3 · Cited by 101 · see citing works
Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
Miranda, A. M., Ashok, A., Chan, R. B., Zhou, B., Xu, Y., McIntire, L. B., Area-Gomez, E., Di Paolo, G., Duff, K. E., Oliveira, T. G., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01881-6 · Cited by 60 · see citing works
Fagan, A. M., Christopher, E., Taylor, J. W., Parsadanian, M., Spinner, M., Watson, M., Fryer, J. D., Wahrle, S., Bales, K. R., Paul, S. M., et al. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63399-8 · Cited by 54 · see citing works
Self-citationApolipoprotein E decreases tau kinases and phospho-tau levels in primary neurons.
Hoe, H.-S., Freeman, J., & Rebeck, G. W. (2006) · Molecular Neurodegeneration · doi:10.1186/1750-1326-1-18 · Cited by 45 · see citing works
Sharman, M. J., Shui, G., Fernandis, A. Z., Lim, W. L. F., Berger, T., Hone, E., Taddei, K., Martins, I. J., Ghiso, J., Buxbaum, J. D., et al. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1348 · Cited by 35 · see citing works
- Authors
- Han, X., Cheng, H., Fryer, J. D., Fagan, A. M., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Han, Xianlin
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 278
- Issue
- 10
- Pages
- 8043-8051
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1967757559
- Cited by
- 126
- References
- 9
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 10 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 5 · 2013: 10 · 2012: 4
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P 50 AG05681, P50AG005681, AG13956)
- National Center for Research Resources (M01-RR00036, M01RR000036)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, sulfatide, brain lipid metabolism, cerebrospinal fluid, ApoE-deficient mice, APOE3, high-density lipoprotein, hippocampus, cerebral cortex, sphingolipids, cholesterol, phospholipids, Alzheimer's disease, brain injury recovery
- MeSH terms
- Animals, Apolipoproteins E, Brain, Humans, Mice, Inbred C57BL, Mice, Transgenic, Sulfoglycosphingolipids, Spectrometry, Mass, Electrospray Ionization, Mice, Apolipoprotein E3, Apolipoprotein E4
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