Clusterin levels are increased in Alzheimer's disease and influence the regional distribution of A beta

摘要

Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates A fibril formation and toxicity and facilitates amyloid-beta (A) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of A, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, A beta 40 and A beta 42 by sandwich ELISA in brain regions with a predilection for amyloid pathologymid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH), and regions with little or no pathologythalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of A. It was significantly higher in AD than controls, and correlated positively with A beta 42 and insoluble A beta 40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy, and in MF and PC regions was highest in APOE 4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with A level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble A beta 42; however, the molar ratio of clusterin : A beta 42 declined with insoluble A beta 42 level in a region-dependent manner, being lowest in regions with predilection for A plaque pathology. Under physiological conditions, clusterin reduces aggregation and promotes clearance of A. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant A beta, but because the increase does not match the rising level of A beta 42, the molar ratio of clusterin : A beta 42 in those regions falls, probably contributing to A deposition within the tissue.