Journal
JOURNAL OF NEUROCHEMISTRY
Volume 132, Issue 4, Pages 477-486Publisher
WILEY
DOI: 10.1111/jnc.12937
Keywords
Alzheimer's disease; amyloid; BACE inhibitor; neural plaque; neurological disorder; secretase
Categories
Funding
- Swedish Research Council
- Hjarnfonden
- Swedish Cancer Society
- Karolinska Institutet
- Knut and Alice Wallenbergs Stiftelse
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Aggregation of amyloid beta (A beta) peptides and the subsequent neural plaque formation is a central aspect of Alzheimer's disease. Various strategies to reduce A beta load in the brain are therefore intensely pursued. It has been hypothesized that reducing A beta peptides in the periphery, that is in organs outside the brain, would be a way to diminish A beta levels and plaque load in the brain. In this report, we put this peripheral sink hypothesis to test by investigating how selective inhibition of A beta production in the periphery using a beta-secretase (BACE) 1 inhibitor or reduced BACE1 gene dosage affects Ab load in the brain. Selective inhibition of peripheral BACE1 activity in wildtype mice or mice over-expressing amyloid precursor protein (APPswe transgenic mice; Tg2576) reduced A beta 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 A beta levels in both brain and periphery already after acute dosing. Mice heterozygous for BACE1, displayed a 62% reduction in plasma A beta 40, whereas brain A beta 40 was only lowered by 11%. These data suggest that reduction of A beta in the periphery is not sufficient to reduce brain A beta levels and that BACE1 is not the rate-limiting enzyme for A beta processing in the brain. This provides evidence against the peripheral sink hypothesis and suggests that a decrease in A beta via BACE1 inhibition would need to be carried out in the brain.
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