Activity of P-Glycoprotein, a β-Amyloid Transporter at the Blood-Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease.
Activity of P-Glycoprotein, a β-Amyloid Transporter at the Blood-Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease.
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DOI：
10.2967/jnumed.113.130161
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发表时间：
2014-07
期刊：
影响因子：
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通讯作者：
Unadkat JD
中科院分区：
文献类型：
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作者：
Deo AK;Borson S;Link JM;Domino K;Eary JF;Ke B;Richards TL;Mankoff DA;Minoshima S;O'Sullivan F;Eyal S;Hsiao P;Maravilla K;Unadkat JD
Animal and histopathological studies of human brain support a role for P-glycoprotein (P-gp) in clearance of cerebral β-amyloid (Aβ) across the blood brain barrier (BBB). We tested the hypothesis that BBB P-gp activity is diminished in Alzheimer’s disease (AD) by accounting for AD-related reduction in regional cerebral blood flow (rCBF). We compared P-gp activity in mild AD patients (n=9) and cognitively normal, age-matched controls (n=9) using positron emission tomography (PET) with a labeled P-gp substrate, [11C]-verapamil, and [15O]-water to measure rCBF. BBB P-gp activity was expressed as the [11C]-verapamil radioactivity extraction ratio (ER={[11C]-verapamil brain distributional clearance, K1}/rCBF). Compared to controls, BBB P-gp activity was significantly lower in the parietotemporal, frontal, posterior cingulate cortices and hippocampus of mild AD subjects. BBB P-gp 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-gp activity and suggests that impaired P-gp activity may contribute to cerebral Aβ accumulation in AD. P-gp induction/activation to increase cerebral Aβ clearance could constitute a novel preventive or therapeutic strategy for AD.
