Extracellular chaperones modulate the effects of Alzheimer’s patient cerebrospinal fluid on Aβ1-42 toxicity and uptake

Abstract

Alzheimer's disease is characterised by the inappropriate death of brain cells and accumulation of the Abeta peptide in the brain. Thus, it is possible that there are fundamental differences between Alzheimer's disease patients and healthy individuals in their abilities to clear Abeta from brain fluid and to protect neurons from Abeta toxicity. In the present study, we examined (1) the cytotoxicity of Alzheimer's disease cerebrospinal fluid (CSF) compared to control CSF, (2) the ability of Alzheimer's disease and control CSF to protect cells from Abeta toxicity and to promote cell-mediated clearance of Abeta and lastly (3) the effects of extracellular chaperones, normally found in CSF, on these processes. We show that the Alzheimer's disease CSF samples tested were more toxic to cultured neuroblastoma cells than normal CSF. In addition, the Alzheimer's disease CSF samples tested were less able to protect cells from Abeta-induced toxicity and less efficient at promoting macrophage-like cell uptake when compared to normal CSF. The addition of physiologically relevant concentrations of the extracellular chaperones, clusterin, haptoglobin and alpha(2)-macroglobulin into CSF protected neuroblastoma cells from Alphabeta(1-42) toxicity and promoted Alphabeta(1-42) uptake in macrophage-like cells. These results suggest that extracellular chaperones are an important element of a system of extracellular protein folding quality control that protects against Abeta toxicity and accumulation.