Lack of brain-to-blood efflux transport activity of low-density lipoprotein receptor-related protein-1 (LRP-1) for amyloid-β peptide(1-40) in mouse: Involvement of an LRP-1-independent pathway

The contribution of low-density lipoprotein receptor-related protein-1 (LRP-1) to the brain-to-blood amyloid-β peptide (Aβ) efflux transport across the blood-brain barrier (BBB) remains controversial. The purpose of the present study was to clarify whether or not LRP-1 plays a role in efflux transport of Aβ at the BBB. After microinjection of [¹²⁵I] activated α2-macroglobulin (α2M), a typical LRP-1 ligand, into mouse secondary somatosensory cortex region under ketamine-xylazine anesthesia, residual radioactivity was not significantly decreased up to 90 min, whereas after microinjection of [¹²⁵I]human Aβ(1-40) [hAβ(1-40)], the residual radioactivity decreased time-dependently. Co-administration of receptor-associated protein, an inhibitor of LRP-1, did not influence [ ¹²⁵I]hAβ(1-40) elimination from mouse brain, suggesting that members of the LDL receptor gene family, including LRP-1, do not contribute to hAβ(1-40) elimination from mouse brain across the BBB. There was no significant difference between the uptakes of [¹²⁵I]activated α2M and [¹⁴C]inulin by mouse brain slices, suggesting that activated α2M was not significantly bound to and&or taken up by parenchymal cells. In conclusion, our results show that LRP-1 does not play a significant role in the brain-to-blood efflux transport of Aβ(1-40) at the mouse BBB, but an unidentified transporter(s) appears to be involved.