Revisiting the peripheral sink hypothesis: inhibiting BACE1 activity in the periphery does not alter ß-amyloid levels in the CNS.
J Neurochem
; 132(4): 477-86, 2015 Feb.
Article
em En
| MEDLINE
| ID: mdl-25156639
ABSTRACT
Aggregation of amyloid beta (Aß) peptides and the subsequent neural plaque formation is a central aspect of Alzheimer's disease. Various strategies to reduce Aß load in the brain are therefore intensely pursued. It has been hypothesized that reducing Aß peptides in the periphery, that is in organs outside the brain, would be a way to diminish Aß levels and plaque load in the brain. In this report, we put this peripheral sink hypothesis to test by investigating how selective inhibition of Aß production in the periphery using a ß-secretase (BACE)1 inhibitor or reduced BACE1 gene dosage affects Aß 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 Aß 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 Aß levels in both brain and periphery already after acute dosing. Mice heterozygous for BACE1, displayed a 62% reduction in plasma Aß40, whereas brain Aß40 was only lowered by 11%. These data suggest that reduction of Aß in the periphery is not sufficient to reduce brain Aß levels and that BACE1 is not the rate-limiting enzyme for Aß processing in the brain. This provides evidence against the peripheral sink hypothesis and suggests that a decrease in Aß via BACE1 inhibition would need to be carried out in the brain. Aggregation of amyloid beta (Aß) peptides in the brain is a central aspect of Alzheimer's disease. In this study, we demonstrate that inhibition of Aß formation by BACE1 inhibitors needs to be carried out in the brain and that reduction of Aß in the periphery is not sufficient to reduce brain Aß levels. This information is useful for developing future Aß-targeting therapies for Alzheimer's disease.
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Bases de dados:
MEDLINE
Assunto principal:
Encéfalo
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Peptídeos beta-Amiloides
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Ácido Aspártico Endopeptidases
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Secretases da Proteína Precursora do Amiloide
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Animals
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Female
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Humans
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Suécia