A test of the cytosolic apolipoprotein E hypothesis fails to detect the escape of apolipoprotein E from the endocytic pathway into the cytosol and shows that direct expression of apolipoprotein E in the cytosol is cytotoxic
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Genetic evidence indicates that apolipoprotein E4 (apoE4) is a risk factor for the development of Alzheimer’s disease. A controversial hypothesis proposes that apoE, a typical secretory protein, accesses the neuronal cytosol in which apoE3, but not apoE4, protects tau from hyperphosphorylation. However, no conclusive evidence for the presence of apoE in the cytosolic compartment has been presented. We designed a novel assay to test whether apoE can access the cytosol via escape from the endocytic pathway by incorporating a nuclear localization signal (NLS) into apoE. Control experiments demonstrated that apoE plus NLS (apoE+NLS) is chaperoned to the nucleus if it reaches the cytosolic compartment. When exogenous apoE+NLS was endocytosed by neuronal cells, no nuclear apoE was detected, indicating that apoE remains within the endocytic pathway and does not escape into the cytosol. Furthermore, we show that direct cytosolic expression of apoE is cytotoxic. These data argue that effects of apoE on the neuronal cytoskeleton and on neurite outgrowth are not mediated via cytosolic interactions but rather by actions originating at the cell surface.
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There is currently no conclusive evidence demonstrating localization of apoE to the neuronal cytosol, where the majority of tau exists under normal conditions.
“However, there is currently no conclusive evidence demonstrating localization of apoE to the neuronal cytosol, where the majority of tau exists under normal conditions (DeMattos et al., 1999).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as DeMattos et al., 1999
The paper’s introductory passage says that no conclusive evidence had been presented for apoE in the cytosolic compartment, and the Discussion calls prior neuronal staining data inconclusive. The passages do not establish the added claim that most tau normally resides in the neuronal cytosol. (LLM, conf=0.85)
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Cites
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The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
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Nakamura, T., Watanabe, A., Fujino, T., Hosono, T., & Michikawa, M. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-35 · Cited by 124 · 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
Marques, M. A., Owens, P. A., & Crutcher, K. A. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:24:1:073 · Cited by 29 · see citing works
- Authors
- DeMattos, R. B., Thorngate, F. E., & Williams, D. L.
- Affiliations
- Stony Brook University (US)
- ORCID
- DeMattos, Ronald B.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1999-04-01
- Volume
- 19
- Issue
- 7
- Pages
- 2464-2473
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6786055
- OpenAlex
- W2153669909
- Cited by
- 30
- References
- 5
- Citations by year
- 2022: 1
- FWCI
- 3.10
- 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
- National Heart, Lung, and Blood Institute (HL 32868, R01HL032868)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007521)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, Alzheimer's disease, endocytic pathway, nuclear localization signal, neuronal cytotoxicity, tau hyperphosphorylation, neurite outgrowth, neuronal cytoskeleton, cell surface signaling
- MeSH terms
- Apolipoproteins E, Cell Line, Cell Nucleus, Cell Survival, Cytosol, Endocytosis, Humans, Immunohistochemistry, Risk Factors, Transfection
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