Increased neurotoxicity of high‐density lipoprotein secreted from murine reactive astrocytes deficient in a peroxisomal very‐long‐chain fatty acid transporter Abcd1

Abstract X‐linked adrenoleukodystrophy (X‐ALD) is a genetic neurodegenerative disorder caused by pathogenic variants in ABCD1 , resulting in the accumulation of very‐long‐chain fatty acids (VLCFAs) in tissues. The etiology of X‐ALD is unclear. Activated astrocytes play a pathological role in X‐ALD. Recently, reactive astrocytes have been shown to induce neuronal cell death via saturated lipids in high‐density lipoprotein (HDL), although how HDL from reactive astrocytes exhibits neurotoxic effects has yet to be determined. In this study, we obtained astrocytes from wild‐type and Abcd1 ‐deficient mice. HDL was purified from the culture supernatant of astrocytes, and the effect of HDL on neurons was evaluated in vitro. To our knowledge, this study shows for the first time that HDL obtained from Abcd1‐ deficient reactive astrocytes induces a significantly higher level of lactate dehydrogenase (LDH) release, a marker of cell damage, from mouse primary cortical neurons as compared to HDL from wild‐type reactive astrocytes. Notably, HDL from Abcd1‐ deficient astrocytes contained significantly high amounts of VLCFA‐containing phosphatidylcholine (PC) and LysoPC. Activation of Abcd1‐ deficient astrocytes led to the production of HDL containing decreased amounts of PC with arachidonic acid in sn ‐2 acyl moieties and increased amounts of LysoPC, presumably through cytosolic phospholipase A 2 α upregulation. These results suggest that compositional changes in PC and LysoPC in HDL, due to Abcd1 deficiency and astrocyte activation, may contribute to neuronal damage. Our findings provide novel insights into central nervous system pathology in X‐ALD.