Cytotoxicity of Amyloid β1-42 Fibrils to Brain Immune Cells

Abstract

Alzheimer's disease (AD) is a progressive pathology that is linked to abrupt aggregation of amyloid β1-42 (Aβ1-42) peptide in the central nervous system. Aβ1-42 aggregation yields amyloid oligomers and fibrils, toxic protein aggregates that cause progressive neuronal degeneration in the frontal lobe of the brain. Although neurons remain the focus of AD for decades, a growing body of evidence suggests that the degeneration of immune cells in the brain can be the major cause of AD. However, the extent to which Aβ1-42 aggregates are toxic to the major classes of immune cells in the brain remains unclear. In the current study, we examine the cytotoxic effects of Aβ1-42 fibrils on macrophages, dendritic cells, and microglia. These cells play vitally important roles in development and homeostasis of the central nervous system. We found that Aβ1-42 fibrils caused calcium release and enhanced levels of reactive oxygen species in macrophages, dendritic cells, and microglia as well as neurons. We also investigated the extent to which the lysozymes of these immune cells could alter the aggregation properties of Aβ1-42. Our results showed that lysosomes extracted from macrophages, dendritic cells, and microglia drastically accelerated Aβ1-42 aggregation as well as altered cytotoxicity of these protein aggregates. These results indicate that impairment of immune cells in the brain can be a critically important aspect of neurodegenerative processes that are taking place upon the onset of AD.