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, MDR1Aknockout
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.
Keywords: Alzheimer’s disease, amyloid β -peptide, blood-brain barrier, blood-cerebrospinal fluid barrier, MDR1,
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