APOLIPOPROTEIN J/CLUSTERIN IS THE PRIMARY DETERMINANT OF THE CHOLESTEROL EFFLUX CAPACITY OF CEREBROSPINAL FLUID

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Cholesterol has been implicated in the pathogenesis of Alzheimer's disease (AD). We seek out to encompass cholesterol contribution to AD in a metric suitable for application to human cohorts. To this end, we used the concept and assay for cholesterol efflux capacity of high-density lipoprotein (HDL) (CEC HDL), a metric that predicts atherosclerotic cardiovascular disease, as a paradigm to develop an analogous metric, CEC of cerebrospinal fluid (CEC CSF), for research and diagnostic purposes in AD. In the CEC HDL assay, radiocholesterol-labeled J774 macrophages are exposed to human HDL; radiocholesterol released to HDL is expressed as the percentage of the released and cell-retained radiocholesterol; efflux to sample HDL is divided by efflux to a standard HDL to derive CEC HDL values. Different cell types express cholesterol efflux transporters at varying levels. Macrophage is the most critical cell type in atherogenesis. Several cell types could be critical to AD. Neural SH-SY5Y, astrocyte A172, microglial N9 and J774 (control) cells were treated as in the CEC HDL assay and then exposed to CSF. CECs CSF for SH-SY5Y, A172, N9 and J774 cells were calculated as above. Commercially purchased and throwaway CSF samples (25 in total) were used in this study. SH-SY5Y, A172 and N9 cells expressed ABCA1, ABCG1, SR-B1 and ABCG4 and released cholesterol to apolipoprotein A-I (apo A-I) and HDL, albeit at lower levels compared to J774. CECs CSF varied 2-3X between the lowest and highest values. Remarkably, CECs CSF for N9 microglia and for J774 macrophages were nearly identical (R2=0.94; P<0.0001). CECs CSF for SH-SY5Y, A172 and N9 cells were correlated with one another less (R2=0.66-0.78; P<0.0001). CECs CSF for SH-SY5Y, A172 and N9 were strongly correlated with CSF apo A-I (R2=0.42-0.7) and apo J (R2=0.73-0.85) and weakly correlated with apo E (R2=0.28-0.39). After adjustment for apo J, the association between CECs CSF and apo A-I was no longer significant. CECs CSF for SH-SY5Y, A172 and N9 cells exhibit notable variability from individual to individual and from one and another and are determined mainly by CSF apo J levels.