P2‐347: Absence of MDR‐1 P‐glycoprotein at the blood‐brain barrier increased the passage of blood‐borne exogenous Aβ peptides across the BBB into the brain

Alzheimer's disease (AD) is characterized by accumulation and deposition of Aβ peptides in the brain. Experimental studies showed that Aβ can be transported across blood-brain barrier (BBB). Aberrant Aβ transport across BBB may contribute to accumulation and deposition of Aβ in the brain. Some studies suggested that mis-folded Aβ can be transmitted via transfusion from donors to recipients, which may be a risk factor of AD pathogenesis. Several transporters/receptors are involved in Aβ transport across BBB. MDR-1 P-glycoprotein/ABCB1 (Pgp) is highly expressed in cerebroendothelial cells and acts as a major drug transporter at the BBB. Pgp was shown to play a substantial role in Aβ elimination from brain. However, it is unknown whether Pgp can prevent blood-borne exogenous Aβ from entering the brain. In the present study, we investigated the role of Pgp in the passage of blood-borne Aβ across the BBB into the brain. Cy5.5-labeled Aβ1-40 or Cy5.5 free-dye were injected intravenously into mdr-1a/b knockout (Pgp-null) and wild-type (wt) mice. The mice were scanned alive with a time-domain optical imager eXplore Optix at 2, 4, 6, and 8h post-injection for Cy5.5 fluorescence accumulation in the brain. Mice were sacrificed at 8h and their ex vivo brains were scanned. The concentration of Cy5.5 fluorescence in the heads of Pgp-null mice was higher at 4 time-points than that in wt mice injected with the same amount of Cy5.5-labeled Aβ1-40 (Pgp-null/wt mice: 2h: 124.61%/100%; 4h: 126.21%/100%; 6h: 116.03%/100%; 8h: 141.28%/100%). The fluorescent concentration in the ex vivo brain was also higher in Pgp-null mice (109.33%) than wt (100%). Two pairs of Pgp-null mice were injected with either Cy5.5-labeled Aβ peptides or Cy5.5 free-dye in equal fluorescent intensity and their ex vivo brains were scanned at 8h. The two Pgp-null mice injected with Cy5.5-labeled Aβ had about 1.5-fold higher fluorescence in their brains than the Pgp-null mice injected with Cy5.5 free-dye in equal fluorescent intensity, suggesting that Cy5.5-labeled Aβ peptides easily trans-passed BBB into brain than Cy5.5 free-dye in Pgp-null mice. These results indicate that the absence of Pgp at the BBB increased the passage of blood-borne exogenous Aβ across the BBB into the brain.

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