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Revisiting the peripheral sink hypothesis: inhibiting BACE 1 activity in the periphery does not alter β‐amyloid levels in the CNS
Author(s) -
Georgievska Biljana,
Gustavsson Susanne,
Lundkvist Johan,
Neelissen Jan,
Eketjäll Susanna,
Ramberg Veronica,
Bueters Tjerk,
Agerman Karin,
Juréus Anders,
Svensson Samuel,
Berg Stefan,
Fälting Johanna,
Lendahl Urban
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12937
Subject(s) - genetically modified mouse , amyloid precursor protein , peripheral , amyloid precursor protein secretase , chemistry , amyloid (mycology) , amyloid beta , transgene , pharmacology , alzheimer's disease , biology , biochemistry , medicine , disease , peptide , gene , inorganic chemistry
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 BACE 1 gene dosage affects Aβ load in the brain. Selective inhibition of peripheral BACE 1 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 BACE 1 inhibitor with improved brain disposition reduced Aβ levels in both brain and periphery already after acute dosing. Mice heterozygous for BACE 1, 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 BACE 1 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 BACE 1 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.