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  • Title: Revisiting the peripheral sink hypothesis: inhibiting BACE1 activity in the periphery does not alter β-amyloid levels in the CNS.
    Author: Georgievska B, Gustavsson S, Lundkvist J, Neelissen J, Eketjäll S, Ramberg V, Bueters T, Agerman K, Juréus A, Svensson S, Berg S, Fälting J, Lendahl U.
    Journal: J Neurochem; 2015 Feb; 132(4):477-86. PubMed ID: 25156639.
    Abstract:
    Aggregation of amyloid beta (Aβ) peptides and the subsequent neural plaque formation is a central aspect of Alzheimer's disease. Various strategies to reduce Aβ load in the brain are therefore intensely pursued. It has been hypothesized that reducing Aβ peptides in the periphery, that is in organs outside the brain, would be a way to diminish Aβ levels and plaque load in the brain. In this report, we put this peripheral sink hypothesis to test by investigating how selective inhibition of Aβ production in the periphery using a β-secretase (BACE)1 inhibitor or reduced BACE1 gene dosage affects Aβ load in the brain. Selective inhibition of peripheral BACE1 activity in wild-type mice or mice over-expressing amyloid precursor protein (APPswe transgenic mice; Tg2576) reduced Aβ levels in the periphery but not in the brain, not even after chronic treatment over several months. In contrast, a BACE1 inhibitor with improved brain disposition reduced Aβ levels in both brain and periphery already after acute dosing. Mice heterozygous for BACE1, displayed a 62% reduction in plasma Aβ40, whereas brain Aβ40 was only lowered by 11%. These data suggest that reduction of Aβ in the periphery is not sufficient to reduce brain Aβ levels and that BACE1 is not the rate-limiting enzyme for Aβ processing in the brain. This provides evidence against the peripheral sink hypothesis and suggests that a decrease in Aβ via BACE1 inhibition would need to be carried out in the brain. Aggregation of amyloid beta (Aβ) peptides in the brain is a central aspect of Alzheimer's disease. In this study, we demonstrate that inhibition of Aβ formation by BACE1 inhibitors needs to be carried out in the brain and that reduction of Aβ in the periphery is not sufficient to reduce brain Aβ levels. This information is useful for developing future Aβ-targeting therapies for Alzheimer's disease.
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