title: Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice.
abstract: In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.
authors: Department of Neurology, Neurodegeneration Research Laboratory, University of Rostock, Rostock, Germany.
authors: Markus
authors: M
authors: Krohn
authors: Cathleen
authors: C
authors: Lange
authors: Jacqueline
authors: J
authors: Hofrichter
authors: Katja
authors: K
authors: Scheffler
authors: Jan
authors: J
authors: Stenzel
authors: Johannes
authors: J
authors: Steffen
authors: Toni
authors: T
authors: Schumacher
authors: Thomas
authors: T
authors: Brüning
authors: Anne-Sophie
authors: AS
authors: Plath
authors: Franziska
authors: F
authors: Alfen
authors: Anke
authors: A
authors: Schmidt
authors: Felix
authors: F
authors: Winter
authors: Katja
authors: K
authors: Rateitschak
authors: Andreas
authors: A
authors: Wree
authors: Jörg
authors: J
authors: Gsponer
authors: Lary C
authors: LC
authors: Walker
authors: Jens
authors: J
authors: Pahnke
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055806:Microvessels / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1