Alzheimer disease and the blood brain barrier: is Abeta transport the key?
Increased production of the amyloid-beta (Abeta) peptide can lead to Abeta aggregation and buildup in the brain and rare familial forms of early onset Alzheimer disease (AD). Aggregation and buildup of Abeta also appears to contribute to the common, late-onset form of AD, which accounts for 99% of cases, however, there is not strong evidence of Abeta over-production in late-onset AD.
This suggests that there is an age-associated alteration in brain Abeta clearance that contributes to late-onset AD. There is substantial clearance of Abeta from the brain to the blood via the blood-brain-barrier (BBB). Thus, understanding which molecules at the BBB are responsible for Abeta clearance is important. Several transporters have been identified on the BBB that mediate Abeta efflux, however if and how these transporters contribute to Abeta deposition as plaques remain unclear.
In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, David Holtzman and colleagues from Washington University demonstrate that P-glycoprotein is required for Abeta transport across the BBB and that ablation of this transporter at the BBB increases Abeta deposition in a mouse model of AD.
P-glycoprotein has been a major pharmaceutical target by conferring resistance to many chemotherapy regimens, as well as its role in eliminating a wide variety of medicines via liver uptake. It is possible that chronic treatment with these types of drugs could alter P-glycoprotein function, thereby altering Abeta transport and the risk of developing AD. The findings in this manuscript, in addition to its implications in understanding Abeta transport via the BBB and its therapeutic implications, suggests that researchers should begin to explore whether drugs currently being utilized in humans that affect PgP activity, alter risk for AD.
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