Cerebral Apolipoprotein D Exits the Brain and Accumulates in Peripheral Tissues

Abstract

Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. In rodent, the bulk of its expression occurs in the central nervous system. Despite this, ApoD has profound effects in peripheral tissues, indicating that neural ApoD may reach peripheral organs. We endeavor to determine if cerebral ApoD can reach the circulation and accumulate in peripheral tissues. Three hours was necessary for over 40% of all the radiolabeled human ApoD (hApoD), injected bilaterally, to exit the central nervous system (CNS). Once in circulation, hApoD accumulates mostly in the kidneys/urine, liver, and muscles. Accumulation specificity of hApoD in these tissues was strongly correlated with the expression of lowly glycosylated basigin (BSG, CD147). hApoD was observed to pass through bEnd.3 blood brain barrier endothelial cells monolayers. However, cyclophilin A did not impact hApoD internalization rates in bEnd.3, indicating that ApoD exit from the brain is either independent of BSG or relies on additional cell types. Overall, our data showed that ApoD can quickly and efficiently exit the CNS and reach the liver and kidneys/urine, organs linked to the recycling and excretion of lipids and toxins. This indicated that cerebral overexpression during neurodegenerative episodes may serve to evacuate neurotoxic ApoD ligands from the CNS.

The Neuroprotective Lipocalin Apolipoprotein D Stably Interacts with Specific Subtypes of Detergent-Resistant Membrane Domains in a Basigin-Independent Manner

“…Here, we demonstrate a dose-dependent in vitro interaction of ApoD with SH-SY5Y membranes in the absence of native BSG expression, in agreement with the ability of ApoD to exert its function on neurite differentiation in SH-SY5Y cells [ 26 ]. The low proportion of LG-BSG vs. HG-BSG reported in both mouse brain [ 38 ] and the astrocytic line 1321N1, tested in this work, add doubts to its requirement as ApoD receptor. Moreover, brain endothelial cells, with significant levels of LG-BSG expression, are able to transcytose ApoD in a BSG-independent manner [ 38 ].…”

“…The low proportion of LG-BSG vs. HG-BSG reported in both mouse brain [ 38 ] and the astrocytic line 1321N1, tested in this work, add doubts to its requirement as ApoD receptor. Moreover, brain endothelial cells, with significant levels of LG-BSG expression, are able to transcytose ApoD in a BSG-independent manner [ 38 ]. Finally, the physical interaction of ApoD and specific subdomains in plasma and lysosomal membranes of glial and neuronal cells do not require BSG, although the two proteins might share some of these membrane compartments.…”

“…The low-glycosylated form of the membrane glycoprotein BSG has been reported as a ApoD receptor [ 20 ]. Low and high-glycosylation forms of BSG (LG-BSG and HG-BSG) are present in different proportions in several cell types [ 25 , 35 – 37 ], while HG-BSG is the most abundant isoform in the mouse brain [ 38 ]. 1321N1 cells show HG-BSG as the major BSG form, although small amounts of LG-BSG are detected (Fig.…”

Apolipoprotein D in Oxidative Stress and Inflammation

“…Despite the fact that the exact internalization process of ApoD has yet to be clearly demonstrated, studies using different cells (HEK293T, 1321N1, U87, NIH/3T3 and primary murine astrocytes [7,55,60,62]) and mice model [58] demonstrate ApoD's potential to be internalize and/or trafficked.…”

“…Previous studies have identified Basigin (BSG) as one of the receptors responsible for ApoD's intracellular internalization and whole body distribution in mice [57,58]. BSG-KO glioblastoma U87 cells have recently been used to verify the role of BSG for ApoD's internalisation [62], but have also been used in parallel to evaluate the effect of ApoD on the level of LPO upon paraquat treatment.…”