Revisiting the peripheral sink hypothesis: inhibiting BACE1 activity in the periphery does not alter β‐amyloid levels in the CNS

Abstract

Aggregation of amyloid beta (Ab) peptides and the subsequent neural plaque formation is a central aspect of Alzheimer's disease. Various strategies to reduce Ab load in the brain are therefore intensely pursued. It has been hypothesized that reducing Ab peptides in the periphery, that is in organs outside the brain, would be a way to diminish Ab levels and plaque load in the brain. In this report, we put this peripheral sink hypothesis to test by investigating how selective inhibition of Ab production in the periphery using a b-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 Ab 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 Ab levels in both brain and periphery already after acute dosing. Mice heterozygous for BACE1, displayed a 62% reduction in plasma Ab40, whereas brain Ab40 was only lowered by 11%. These data suggest that reduction of Ab in the periphery is not sufficient to reduce brain Ab levels and that BACE1 is not the rate-limiting enzyme for Ab processing in the brain. This provides evidence against the peripheral sink hypothesis and suggests that a decrease in Ab via BACE1 inhibition would need to be carried out in the brain.

BACE1 across species: a comparison of the in vivo consequences of BACE1 deletion in mice and rats

“…This suggests that in rodents, endogenous BACE1 levels are well above the levels necessary for APP processing. These findings demonstrate that the biochemical consequences of BACE1 deletion, at least with respect to APP processing, are consistent between rats and mice42434445 and in alignment with observations in humans following treatment with BACE1 inhibitors46474849, suggesting that this rat model has adequate predictive validity as a translational model in these measures.…”

Association of plasma β-amyloid with MRI markers of structural brain aging the 3-City Dijon study

“…For example, it has been suggested that cerebral Ab accumulation may be partly a downstream consequence of age or vascular diseaseerelated microvascular injury (Sagare et al, 2013). Alternative theories have also been substantiated by studies demonstrating differential impact of anti-Ab antibodies on Ab levels in the blood and peripheral blood suggesting that soluble AB may need to be depleted within the central nervous system instead of the peripheral blood system (Georgievska et al, 2014;Henderson et al, 2014).…”

“…Methods of voxel-based morphometry used to estimate brain tissue volumes have been previously described (Godin et al, 2009;Lemaitre et al, 2005b). Images were sent to the database repository.…”

Platelets are responsible for the accumulation of β-amyloid in blood clots inside and around blood vessels in mouse brain after thrombosis

“…This peripheral sink hypothesis is based on the influx–efflux transport across the brain vessel walls into the blood stream. It was shown in recent work that continued inhibition of peripheral BACE1 affects the brain levels of Aβ much less than the peripheral levels [59]. In addition, degrading Aβ only peripherally with neprilysin does not affect the central levels of Aβ [60].…”