Cytotoxicityof Amyloid β1–42 Fibrilsto Brain Immune Cells

Alzheimer’s disease (AD) is a progressive pathology that is linked to abrupt aggregation of amyloid β_1–42 (Aβ_1–42) peptide in the central nervous system. Aβ_1–42 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 Aβ_1–42 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 Aβ_1–42 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 Aβ_1–42 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 Aβ_1–42. Our results showed that lysosomes extracted from macrophages, dendritic cells, and microglia drastically accelerated Aβ_1–42 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.