A Role for P-Glycoprotein in Clearance of Alzheimer Amyloid ? -Peptide from the Brain

Abstract

Most data indicates that Alzheimer’s disease involves an accumulation of amyloid β-peptide (Aβ) in the CNS and that sporadic cases arise from a deficiency in Aβ clearance. Considerable attention has been given to mechanisms by which Aβ might be transported between the brain and blood, and evidence suggests that p-glycoprotein, also known as the multi-drug resistance (MDR) protein (product of the ABCB1 gene), plays a role in Aβ transport across the blood-brain barrier (BBB). We tested this possibility through two approaches: First, wild-type and MDR1A-knockout mice were compared after intravenous injection of [125I]-labeled Aβ; after 60 min, homogenates of brain parenchyma were subjected to γ-counting of TCA-precipitable material, and histological sections of brain were subjected to autoradiography. Second, MDR1A-knockout mice were crossed with Tg2576 APP transgenic mice, a line that routinely accumulates Aβ in the brain; SDS and formic acid extracts of brain homogenates were assessed for Aβ levels by ELISA. Each of these approaches yielded data indicating that Aβ accumulates to a greater degree in mice lacking MDR1A. These findings confirm other reports linking p-glycoprotein to Aβ clearance across the BBB and have important implications for Alzheimer’s disease genetics, pharmacology, and epidemiology.

P‐glycoprotein: a role in the export of amyloid‐β in Alzheimer's disease?

“…LRP‐1 expression was not examined in the aforementioned study by Wang et al . . This interrelationship between LRP‐1 and P‐gp has also been suggested in other studies.…”

“…Similarly, when Abcb1a À/À mice were crossed with Tg2576 mice to produce a double transgenic model, absence of the Abcb1a gene product was sufficient to significantly compromise [ 125 I]-Ab 40 clearance from the brain. The authors additionally noted that only soluble Ab was affected by the absence of P-gp, whereas the formic acid fraction of brain homogenate, which represents insoluble Ab fibrils, was unaffected [71]. These results support findings by Cirrito et al who observed that Ab deposition in 12-month-old Tg2576 Abcb1a/ b À/À double-knockout mice was significantly greater than in Tg2576 mice with intact P-gp.…”

“…Critically, however, it was noted that the P-gp-silencing was accompanied by a 51% reduction in brain capillary LRP-1 expression compared to wild-type mice, leaving the authors unable to conclude whether this LRP-1 suppression also contributed to the impaired Ab efflux. LRP-1 expression was not examined in the aforementioned study by Wang et al [71]. This interrelationship between LRP-1 and P-gp has also been suggested in other studies.…”

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“…27,28 Additionally, the efflux transporter permeability glycoprotein (P-gp), which is located on brain capillary endothelial cells in the BBB and belongs to the adenosine-triphosphate-binding cassette B1 transporter family contributes to the elimination of Aβ 1-40 and Aβ 1-42 from the brain across the BBB. [29][30][31][32] In agreement with this, recent evidence suggests that decreased transport activity of P-gp is associated with increased levels of Aβ in aged humans and in the specific brain regions affected in AD patients. 29 These findings together suggest the important role of Aß transport across the BBB in the pathogenesis of AD.…”

“…It has already been demonstrated that low‐ density lipoprotein receptor‐related protein 1 (LRP1) reveals a diverse modifying effect on amyloid trafficking in the brain . Additionally, the efflux transporter permeability glycoprotein (P‐gp), which is located on brain capillary endothelial cells in the BBB and belongs to the adenosine‐triphosphate‐binding cassette B1 transporter family contributes to the elimination of Aβ 1–40 and Aβ 1–42 from the brain across the BBB . In agreement with this, recent evidence suggests that decreased transport activity of P‐gp is associated with increased levels of Aβ in aged humans and in the specific brain regions affected in AD patients .…”