An Apolipoprotein E4 fragment can promote intracellular accumulation of amyloid peptide beta 42
permalinkJournal of Neurochemistry - 2010-04-20Dafnis I, Stratikos E, Tzinia AK, Tsilibary EC, Zannis VI, Chroni A10.1111/j.1471-4159.2010.06756.xApoE plays a crucial role in lipid transport in circulation and the brain. The
Apolipoprotein E4 isoform is a major risk factor for Alzheimer's disease (AD).
ApoE4 is more susceptible to proteolysis than other
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[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.