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Cited by 118Alzheimer's disease research and treatmentsCellular transport and secretionNeuroinflammation and Neurodegeneration Mechanisms

Internalization of β-Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E

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Saavedra, Lucila, Mohamed, Amany, Ma, Victoria, Kar, Satyabrata, de Chaves, Elena Posse·2007·Journal of Biological Chemistry
DOI 10.1074/jbc.m701823200
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Abstract

Extracellular accumulation of beta-amyloid peptide (Abeta) has been linked to the development of Alzheimer disease. The importance of intraneuronal Abeta has been recognized more recently. Although considerable evidence indicates that extracellular Abeta contributes to the intracellular pool of Abeta, the mechanisms involved in Abeta uptake by neurons are poorly understood. We examined the molecular mechanisms involved in Abeta-(1-42) internalization by primary neurons in the absence of apolipoprotein E. We demonstrated that Abeta-(1-42) is more efficiently internalized by axons than by cell bodies of sympathetic neurons, suggesting that Abeta-(1-42) uptake might be mediated by proteins enriched in the axons. Although the acetylcholine receptor alpha7nAChR, previously suggested to be involved in Abeta internalization, is enriched in axons, our results indicate that it does not mediate Abeta-(1-42) internalization. Moreover, receptors of the low density lipoprotein receptor family are not essential for Abeta-(1-42) uptake in the absence of apolipoprotein E because receptor-associated protein had no effect on Abeta uptake. By expressing the inactive dynamin mutant dynK44A and the clathrin hub we found that Abeta-(1-42) internalization is independent of clathrin but dependent on dynamin, which suggests an endocytic pathway involving caveolae/lipid rafts. Confocal microscopy studies showing that Abeta did not co-localize with the early endosome marker EEA1 further support a clathrin-independent mechanism. The lack of co-localization of Abeta with caveolin in intracellular vesicles and the normal uptake of Abeta by neurons that do not express caveolin indicate that Abeta does not require caveolin either. Instead partial co-localization of Abeta-(1-42) with cholera toxin subunit B and sensitivity to reduction of cellular cholesterol and sphingolipid levels suggest a caveolae-independent, raft-mediated mechanism. Understanding the molecular events involved in neuronal Abeta internalization might identify potential therapeutic targets for Alzheimer disease.

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  • Evidence suggests that internalization of Aβ not associated with ApoE occurs through nonendocytotic mechanisms, based on translocation of cell surface bound Aβ directly to the cytosol, and results in accumulation of Aβ primarily outside the endosomal/lysosomal compartment.

    “In contrast, evidence suggests that internalization of Ab not associated with ApoE occurs through nonendocytotic mechanisms, which are based on the translocation of the cell surface bound Ab directly to the cytosol and results in accumulation of Ab primarily outside the endosomal/lysosomal compartment.28,45,46”

    From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [45]

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  1. Tienari, P. J., Ida, N., Ikonen, E., Simons, M., Weidemann, A., Multhaup, G., Masters, C. L., Dotti, C. G., and Beyreuther, K. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 4125-4130
  2. Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lutjohann, D., Keller, P., Runz, H., Kuhl, S., Bertsch, T., von Bergmann, K., Hennerici, M., Beyreuther, K., and Hartmann, T. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 5856 -5861
  3. Simons, M., Keller, P., De Strooper, B., Beyreuther, K., Dotti, C. G., and Simons, K. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 6460 -6464

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Authors
Saavedra, L., Mohamed, A., Ma, V., Kar, S., & de Chaves, E. P.
Affiliations
University of Alberta (CA)
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2007-12
Volume
282
Issue
49
Pages
35722-35732
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m701823200
OpenAlex
W2014341627
Cited by
118
References
97
Citations by year
2025: 2 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 6 · 2015: 1 · 2014: 8 · 2013: 6 · 2012: 17
FWCI
8.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
University of Alberta
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
beta-amyloid peptide, amyloid-beta 42, apolipoprotein E deficiency, axons, sympathetic neurons, low-density lipoprotein receptor family, dynamin, clathrin-independent endocytosis, caveolae, lipid rafts, cholesterol, sphingolipids, Alzheimer's disease
MeSH terms
Adrenergic Fibers, Alzheimer Disease, Animals, Apolipoproteins E, Axons, Cells, Cultured, Cholera Toxin, Cholesterol, Clathrin, Endocytosis, Peptides, Receptors, Nicotinic, Sphingolipids, Amyloid beta-Peptides, Rats, Sprague-Dawley, Caveolae, Dynamins, Rats, alpha7 Nicotinic Acetylcholine Receptor

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