Isoform‐Specific Modulation by Apolipoprotein E of the Activities of Secreted β‐Amyloid Precursor Protein
Abstract
Abstract: The genes for both the β‐amyloid precursor protein and apolipoprotein E (ApoE) have been linked to Alzheimer's disease. This connection suggests the possibility that these proteins interact physically or functionally. To explore this idea, we focused on the neuroprotective activity of secreted amyloid precursor protein (sAPP) and related signal transduction events. After coincubation with ApoE, sAPP exhibited an enhanced [Ca 2+]i‐lowering activity and enhanced protection against excitotoxicity in rat primary hippocampal neurons. In contrast, the stimulation of phosphoinositide production by sAPP was inhibited by ApoE. Kinetic analyses and coimmunoprecipitation experiments indicated that these actions result from formation of a heteromeric complex between ApoE and sAPP. Furthermore, the ApoE4 isoform, which seems to accelerate the onset of Alzheimer's disease, was less potent than ApoE3 in modifying each activity of sAPP. These data suggest that sAPP‐dependent neuroprotective mechanisms would be compromised in individuals expressing ApoE4, a scenario that may contribute to the development of Alzheimer's disease.
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APOE and APOE3Ch influence both Aβ and tau pathology, either directly or through downstream effects such as neuroinflammation.
“Collectively, these recent findings underscore the influence of APOE and APOE3Ch on both Aβ and tau pathology, either directly or through downstream effects such as neuroinflammation.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [21]
Differences in APOE isoform-specific receptor binding affinity and lipid interactions affect neuroinflammation, tau pathology, and amyloid plaque dynamics.
“Studies indicate that APOE binding is integral to some of these processes [16–20] with differences in APOE isoform-specific receptor binding affinity and lipid interactions affecting neuroinflammation, tau pathology, and amyloid plaque dynamics [21–24].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [21]
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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
Apolipoprotein E and Alzheimer's disease: the protective effects of ApoE2 and E3
Rebeck, G. W., Kindy, M., & LaDu, M. J. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4304 · Cited by 89 · see citing works
ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-β1–42
Trommer, B. L., Shah, C., Yun, S. H., Gamkrelidze, G., Pasternak, E. S., Blaine Stine, W., Manelli, A., Sullivan, P., Pasternak, J. F., & LaDu, M. J. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.08.011 · Cited by 82 · see citing works
Tanriverdi, F., Taheri, S., Ulutabanca, H., Caglayan, A. O., Ozkul, Y., Dundar, M., Selcuklu, A., Unluhizarci, K., Casanueva, F. F., & Kelestimur, F. (2008) · Journal of Neurotrauma · doi:10.1089/neu.2007.0456 · Cited by 77 · see citing works
Tran, K. M., Kwang, N. E., Butler, C. A., Gomez-Arboledas, A., Kawauchi, S., Mar, C., Chao, D., Barahona, R. A., Da Cunha, C., Tsourmas, K. I., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00793-x · Cited by 28 · see citing works
- Authors
- Barger, S. W., & Mattson, M. P.
- Affiliations
- John L. McClellan Memorial Veterans Hospital (US)
- University of Kentucky (US)
- Corresponding author
- Barger, Steven W.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1997-07
- Volume
- 69
- Issue
- 1
- Pages
- 60-67
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2095033458
- Cited by
- 52
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2018: 1 · 2017: 1 · 2013: 2
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- apolipoprotein E, amyloid precursor protein, Alzheimer's disease, APOE ε4, APOE3, neuroprotection, excitotoxicity, intracellular calcium, heteromeric protein complexes, hippocampal neurons, signal transduction
- MeSH terms
- Alleles, Animals, Apolipoproteins E, Calcium, Cells, Cultured, Drug Synergism, Fetus, Hippocampus, Humans, Inositol Phosphates, Isomerism, Kidney, Neurons, Neurotoxins, Transfection, Amyloid beta-Peptides, Neuroprotective Agents, Glutamic Acid, Rats, Apolipoprotein E3, Apolipoprotein E4
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