An apolipoprotein E4 fragment can promote intracellular accumulation of amyloid peptide beta 42
Open Access
- 20 April 2010
- journal article
- research article
- Published by Wiley in Journal of Neurochemistry
- Vol. 115 (4), 873-884
- https://doi.org/10.1111/j.1471-4159.2010.06756.x
Abstract
J. Neurochem. (2010) 115, 873–884. Abstract Apolipoprotein E (apoE) plays a crucial role in lipid transport in circulation and the brain. The apoE4 isoform is a major risk factor for Alzheimer’s disease (AD). ApoE4 is more susceptible to proteolysis than other apoE isoforms and apoE4 fragments have been found in brains of AD patients. These apoE4 fragments have been hypothesized to be involved in the pathogenesis of AD, although the mechanism is not clear. In this study we examined the effect of lipid‐free apoE4 on amyloid precursor protein processing and 40‐amino‐acid Aβ variant and 42‐amino‐acid Aβ variant levels in human neuroblastoma SK‐N‐SH cells. We discovered that a specific apoE4 fragment, apoE4[Δ(166‐299)], can promote the cellular uptake of extracellular 40‐amino‐acid Aβ variant and 42‐amino‐acid Aβ variant either generated after amyloid precursor protein transfection or added exogenously. A longer length fragment, apoE4[Δ(186‐299)], or full‐length apoE4 failed to elicit this effect. ApoE4[Δ(166‐299)] effected a 20% reduction of cellular sphingomyelin levels, as well as changes in cellular membrane micro‐fluidity. Following uptake, approximately 50% of 42‐amino‐acid Aβ variant remained within the cell for at least 24 h, and led to increased formation of reactive oxygen species. Overall, our findings suggest a direct link between two early events in the pathogenesis of AD, apoE4 proteolysis and intraneuronal presence of amyloid beta peptide.Keywords
This publication has 50 references indexed in Scilit:
- Mechanism of Neuronal versus Endothelial Cell Uptake of Alzheimer's Disease Amyloid β ProteinPLOS ONE, 2009
- Biophysical Analysis of Progressive C-Terminal Truncations of Human Apolipoprotein E4: Insights into Secondary Structure and Unfolding PropertiesBiochemistry, 2008
- Review on the APP/PS1KI mouse model: intraneuronal Aβ accumulation triggers axonopathy, neuron loss and working memory impairmentGenes, Brain and Behavior, 2008
- ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brainNeurobiology of Aging, 2007
- Oxidative Stress and Neuronal Adaptation in Alzheimer Disease: The Role of SAPK PathwaysAntioxidants and Redox Signaling, 2003
- Effect of aging on plasma membrane fluidity of rat aortic endothelial cells☆Experimental Gerontology, 1999
- Increased plasma amyloid β protein 1–42 levels in Down syndromeNeuroscience Letters, 1998
- Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset FamiliesScience, 1993
- Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteinsBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1987
- A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATIONCanadian Journal of Biochemistry and Physiology, 1959