ABSTRACT:
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.
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