title: P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer's disease: preliminary observations.
abstract: P-glycoprotein (P-gp), part of the blood-brain barrier, limits drug access to the brain and is the target for therapies designed to improve drug penetration. P-gp also extrudes brain amyloid-beta (Aβ). Accumulation of Aβ is a hallmark of Alzheimer's disease (AD). Aβ accumulates in normal aging and in AD primarily due to decreased Aβ clearance. This is a preliminary report on the relative protein and messenger RNA expression of P-gp in human brains, ages 20-100 years, including AD subjects. In these preliminary studies, cortical endothelial P-gp expression decreased in AD compared with controls (p < 0.001). Trends in P-gp expression in human aging are similar to aging rats. Microvessel P-gp messenger RNA remained unchanged with aging and AD. Aβ plaques were found in 42.8% of normal subjects (54.5% of those older than 50 years). A qualitative analysis showed that P-gp expression is lower than the group mean in subjects older than 75 years but increased if younger. Decreased P-gp expression may be related to Aβ plaques in aging and AD. Downregulating P-gp to allow pharmaceuticals into the central nervous system may increase Aβ accumulation.
authors.affiliation: Department of Neurosurgery, Warren Alpert Medical School, Brown University and Aldrich Neurosurgery Research Laboratories, Rhode Island Hospital, Providence, RI, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chiu
authors.affiliation: Department of Neurosurgery, Warren Alpert Medical School, Brown University and Aldrich Neurosurgery Research Laboratories, Rhode Island Hospital, Providence, RI, USA.
authors.forename: Miles C
authors.initials: MC
authors.lastname: Miller
authors.affiliation: Department of Pathology, Division of Neuropathology, Warren Alpert Medical School, Brown University and Rhode Island Hospital, Providence, RI, USA.
authors.forename: Renée
authors.initials: R
authors.lastname: Monahan
authors.affiliation: Department of Neurosurgery, Warren Alpert Medical School, Brown University and Aldrich Neurosurgery Research Laboratories, Rhode Island Hospital, Providence, RI, USA.
authors.forename: Doreen P
authors.initials: DP
authors.lastname: Osgood
authors.affiliation: Department of Neurosurgery, Warren Alpert Medical School, Brown University and Aldrich Neurosurgery Research Laboratories, Rhode Island Hospital, Providence, RI, USA; Department of Pathology, Division of Neuropathology, Warren Alpert Medical School, Brown University and Rhode Island Hospital, Providence, RI, USA.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Stopa
authors.affiliation: Department of Neurosurgery, Warren Alpert Medical School, Brown University and Aldrich Neurosurgery Research Laboratories, Rhode Island Hospital, Providence, RI, USA. Electronic address: geralds@stanford.edu.
authors.forename: Gerald D
authors.initials: GD
authors.lastname: Silverberg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Aging; Alzheimer's disease; Aβ; Blood-brain barrier; P-glycoprotein