P-glycoprotein (P-gp), an ABC efflux transporter, is highly expressed at the blood brain barrier (BBB). Recently, P-gp has been shown to transport amyloid-2, a protein which accumulates in the brain extracellular fluid in patients with Alzheimer's disease (AD). In sporadic, nonfamilial AD, amyloid-2 accumulates in the brain due to its reduced elimination and not due to its increased production. Therefore, we have hypothesized that the activity of P-gp, which mediates amyloid-2 clearance, is compromised at the BBB in AD patients. We will test this hypothesis by measuring P-gp activity at the BBB in mild-to-moderate AD patients and age-matched cognitively normal volunteers using a noninvasive positron emission tomography (PET) technique recently developed in our laboratories. The importance of P-gp in the clearance of amyloid-2 from the brain creates an exciting therapeutic opportunity to treat AD. P-gp is an inducible transporter and several, well-established approved drugs (e.g. rifampin), can induce P-gp activity. Therefore, our aim will be: To compare P-gp activity at the BBB in Alzheimer patients and in age-matched cognitively normal volunteers (controls), using the non-invasive technology, positron emission tomography (PET). Our studies will utilize an innovative, noninvasive PET imaging technique, developed by our laboratories, to measure P-gp activity at the BBB of patients with AD and age-matched cognitively normal volunteers. The logical progression of our studies from published data to in vivo studies in AD patients will unequivocally determine if P-gp activity is compromised in AD. These proposed studies have the potential to result in identification of P-gp as a novel therapeutic target for the treatment of AD, a disease for which no effective therapy exists.
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