title: ATP-binding cassette transporters P-glycoprotein and breast cancer related protein are reduced in capillary cerebral amyloid angiopathy.
abstract: Alzheimer's disease (AD) is the most common form of dementia and marked by deposition of amyloid-β (Aβ) within the brain. Alterations of Aβ transporters at the neurovasculature may play a role in the disease process. We investigated the expression of ABC transporters P-glycoprotein (P-gp) and breast cancer related protein (BCRP) in non-neurologic controls, AD, and severe capillary cerebral amyloid angiopathy (capCAA) cases, which are characterized by deposition of Aβ within cerebral capillaries. Our data show that microvascular expression of P-gp and BCRP is strikingly decreased in capCAA-affected vessels but not in AD and control samples. Messenger RNA levels of P-gp, but not of BCRP, were downregulated in brain endothelial cells on exposure to oligomeric Aβ42, but not fibrillar Aβ42 or Aβ40. Coincubating Aβ42 together with clusterin, an amyloid-associated protein highly expressed in capCAA-affected vessels, strongly reduced levels of P-gp. In conclusion, accumulation of Aβ, in combination with clusterin, within and around cerebral capillaries, may further aggravate the disease process in AD by affecting P-gp expression. Loss of P-gp expression or activity may serve as a selective biomarker for ongoing capCAA.
authors.affiliation: Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Carrano
authors.forename: Hripsime
authors.initials: H
authors.lastname: Snkhchyan
authors.forename: Gijs
authors.initials: G
authors.lastname: Kooij
authors.forename: Susanne
authors.initials: S
authors.lastname: van der Pol
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.forename: Robert
authors.initials: R
authors.lastname: Veerhuis
authors.forename: Jeroen
authors.initials: J
authors.lastname: Hoozemans
authors.forename: Annemieke
authors.initials: A
authors.lastname: Rozemuller
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015415:Biomarkers; D001921:Brain / Q000098:blood supply*; D002196:Capillaries / Q000166:cytology* / Q000378:metabolism*; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000175:diagnosis / Q000235:genetics*; D051152:Clusterin; D015536:Down-Regulation / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D015415:Biomarkers; D051152:Clusterin; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42)
keywords: ABC transporters; Alzheimer's disease; BCRP; Blood-brain barrier; Cerebral amyloid angiopathy; P-gp