Both isoforms of Drosophila ApoLpp (ApoB) cross the blood–brain barrier in adults

Human ApolipoproteinB (ApoB) exists in two isoforms that are packaged into low density lipoprotein particles and are major contributors to atherosclerosis. Alternatively, Drosophila Apolipoprotein Lipophorin (ApoLpp) also exists in two isoforms packaged into lipoprotein particles that cross the blood-brain barrier (BBB) in second instar larvae where they deliver lipids to neuroblasts. To extend our understanding of ApoLpp function to adult brains and suggest new hypotheses for human ApoB, we document evolutionary conservation between the two N-terminal isoforms human ApoB48 and fly ApoLppII. Then our tissue-specific analyses including rescue of apolpp lethality and apolpp RNAi showed that apolpp expression in the fat body is both necessary and sufficient for survival to adulthood. Our imaging studies of ApoLpp in the adult brain employed endogenous isoform-specific tagged proteins generated by the Fourth Chromosome Resource Project. Images revealed that both ApoLpp isoforms are present in the adult brain with ApoLppII accumulation prominent near glia. Nanobody morphotrap experiments that blocked tagged ApoLpp at the BBB demonstrated that ApoLpp detected inside the adult brain is exogenous. An N- and C-terminal tagged ApoLpp transgene expressed solely in the fat body facilitated tracking of each isoform from fat body secretion to the BBB and then inside the adult brain. Overall, our data suggest that the known role of ApoLpp in lipid delivery to larval brains likely continues in adults. Strong conservation between ApoLppII and ApoB48 supports the hypothesis that ApoB48 may have a role in the brain outside the circulatory system.