Activity of P-Glycoprotein, a β-Amyloid Transporter at the Blood-Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease.
Studies in animals and postmortem human brain tissue support a role for P-glycoprotein in clearance of cerebral β-amyloid across the blood-brain barrier (BBB). We tested the hypothesis that BBB P-glycoprotein activity is diminished in Alzheimer disease (AD) by accounting for an AD-related reduction in regional cerebral blood flow (rCBF).


METHODS
We compared P-glycoprotein activity in mild-AD patients (n = 9) and cognitively normal, age-matched controls (n = 9) using PET with a labeled P-glycoprotein substrate, (11)C-verapamil, and (15)O-water to measure rCBF. BBB P-glycoprotein activity was expressed as the (11)C-verapamil radioactivity extraction ratio ((11)C-verapamil brain distributional clearance, K1/rCBF).


RESULTS
Compared with controls, BBB P-glycoprotein activity was significantly lower in the parietotemporal, frontal, and posterior cingulate cortices and hippocampus of mild AD subjects.


CONCLUSIONS
BBB P-glycoprotein activity in brain regions affected by AD is reduced and is independent of rCBF. This study improves on prior work by eliminating the confounding effect that reduced rCBF has on assessment of BBB P-glycoprotein activity and suggests that impaired P-glycoprotein activity may contribute to cerebral β-amyloid accumulation in AD. P-glycoprotein induction or activation to increase cerebral β-amyloid clearance could constitute a novel preventive or therapeutic strategy for AD.
Department of Pharmaceutics, University of Washington, Seattle, Washington.
Anand K
AK
Deo
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington.
Soo
S
Borson
Department of Radiology, University of Washington, Seattle, Washington.
Jeanne M
JM
Link
Department of Anesthesiology, University of Washington, Seattle, Washington; and.
Karen
K
Domino
Department of Radiology, University of Washington, Seattle, Washington.
Janet F
JF
Eary
Department of Pharmaceutics, University of Washington, Seattle, Washington.
Ban
B
Ke
Department of Radiology, University of Washington, Seattle, Washington.
Todd L
TL
Richards
Department of Radiology, University of Washington, Seattle, Washington.
David A
DA
Mankoff
Department of Radiology, University of Washington, Seattle, Washington.
Satoshi
S
Minoshima
Department of Radiology, University of Washington, Seattle, Washington Department of Statistics, University College Cork, Cork, Ireland.
Finbarr
F
O'Sullivan
Department of Pharmaceutics, University of Washington, Seattle, Washington.
Sara
S
Eyal
Department of Pharmaceutics, University of Washington, Seattle, Washington.
Peng
P
Hsiao
Department of Radiology, University of Washington, Seattle, Washington.
Ken
K
Maravilla
Department of Pharmaceutics, University of Washington, Seattle, Washington jash@u.washington.edu.
Jashvant D
JD
Unadkat
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D016022:Case-Control Studies; D002560:Cerebrovascular Circulation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010104:Oxygen Radioisotopes; D049268:Positron-Emission Tomography; D014700:Verapamil; D014867:Water; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D002250:Carbon Radioisotopes; D010104:Oxygen Radioisotopes; D014867:Water; D014700:Verapamil
Alzheimer’s disease; P-glycoprotein activity; PET imaging; blood–brain barrier; relative extraction ratio