Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Aβ stabilization

Abstract

The brains of individuals with Alzheimer's disease (AD) are characterized by extracellular deposition of β-amyloid protein (Aβ), intracellular neurofibrillary tangles, and loss of neurons. To study molecular markers associated with dying cells in the AD brain, in situ DNA labeling techniques were used to visualize cells with DNA fragmentation. We observed that intracellular accumulation of apolipoprotein E (apoE) is correlated with the detection of intracellular Aβ-like immunoreactivity within the same cytoplasmic granules, suggesting that uptake of lipids may have stabilized the hydrophobic Aβ protein within the cell. These apoE- containing neurons also exhibit high expression of a cell surface receptor, gp330, which is known to bind apoE. Cells containing significant nuclear DNA fragmentation express the highest level of cell surface gp330. Extracellular deposition of Aβ is detected only upon neuronal cell death, initially as halos of Aβ immunoreactivity around individual dying neurons, and subsequently as Aβ plaques containing numerous neuronal cell ghosts. Based on our in situ analysis of nuclear DNA fragmentation, we conclude that neuronal cell death likely occurs before the extracellular deposition of Aβ in AD brains.