Dataset Information

Cerebral amyloid-? proteostasis is regulated by the membrane transport protein ABCC1 in mice.

ABSTRACT: In Alzheimer disease (AD), the intracerebral accumulation of amyloid-? (A?) peptides is a critical yet poorly understood process. A? 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 A? 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 A? clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral A? levels without altering the expression of most enzymes that would favor the production of A? from the A? precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced A? load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of A?, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.

SUBMITTER: Krohn M

PROVIDER: S-EPMC3195473 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice.

Krohn Markus M Lange Cathleen C Hofrichter Jacqueline J Scheffler Katja K Stenzel Jan J Steffen Johannes J Schumacher Toni T Brüning Thomas T Plath Anne-Sophie AS Alfen Franziska F Schmidt Anke A Winter Felix F Rateitschak Katja K Wree Andreas A Gsponer Jörg J Walker Lary C LC Pahnke Jens J

The Journal of clinical investigation 20110901 10

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 transpor ...[more]

PMID: 21881209

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Project description:Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1 This model is described in the article: Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J. J. Clin. Invest. 2011 Oct; 121(10): 3924-3931 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. This model is hosted on BioModels Database and identified by: BIOMD0000000618. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Cerebral amyloid-? proteostasis is regulated by the membrane transport protein ABCC1 in mice.

Publications

Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice.

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