ABCG2 Is Upregulated in Alzheimer's Brain with Cerebral Amyloid Angiopathy and May Act as a Gatekeeper at the Blood-Brain Barrier for Aβ1-40 Peptides

Alzheimer's disease (AD) is characterized by accumulation and deposition of A beta peptides in the brain. A beta deposition in cerebrovessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Since A beta can be transported across blood-brain barrier (BBB), aberrant A beta trafficking across BBB may contribute to A beta accumulation in the brain and CAA development. Expression analyses of 273 BBB-related genes performed in this study showed that the drug transporter, ABCG2, was significantly upregulated in the brains of AD/CAA compared with age-matched controls. Increased ABCG2 expression was confirmed by Q-PCR, Western blot, and immunohistochemistry. Abcg2 was also increased in mouse AD models, Tg-SwDI and 3XTg. A beta alone or in combination with hypoxia/ischemia failed to stimulate ABCG2 expression in BBB endothelial cells; however, conditioned media from A beta-activated microglia strongly induced ABCG2 expression. ABCG2 protein in AD/CAA brains interacted and coimmunoprecipitated with A beta. Overexpression of hABCG2 reduced drug uptake in cells; however, interaction of A beta(1-40) with ABCG2 impaired ABCG2-mediated drug efflux. The role of Abcg2 in A beta transport at the BBB was investigated in Abcg2-null and wild-type mice after intravenous injection of Cy5.5-labeled A beta(1-40) or scrambled A beta(40-1). Optical imaging analyses of live animals and their brains showed that Abcg2-null mice accumulated significantly more A beta in their brains than wild-type mice. The finding was confirmed by immunohistochemistry. These results suggest that ABCG2 may act as a gatekeeper at the BBB to prevent blood A beta from entering into brain. ABCG2 upregulation may serve as a biomarker of CAA vascular pathology in AD patients.