Inhibition of sphingomyelin synthase 1 ameliorates alzheimer-like pathology in APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1.
Exp Neurol
; 311: 67-79, 2019 01.
Article
em En
| MEDLINE
| ID: mdl-30243987
ABSTRACT
Sphingolipids emerge as essential modulators in the etiology of Alzheimer's disease (AD) with unclear mechanisms. Elevated levels of SM synthase 1 (SMS1), which catalyzes the synthesis of SM from ceramide and phosphatidylcholine, have been observed in the brains of Alzheimer's disease (AD), where expression of ß-site APP cleaving enzyme 1 (BACE1), a rate limiting enzyme in amyloid-ß (Aß) generation, are upregulated. In the present study, we show knockdown of SMS1 via andeno associated virus (serotype 8, AAV8) in the hippocampus of APP/PS1 transgenic mice, attenuates the densities of Aß plaques, neuroinflammation, synaptic loss and thus rescuing cognitive deficits of these transgenic mice. We further describe that knockdown or inhibition of SMS1 decreases BACE1 stability, which is accompanied with decreased BACE1 levels in the Golgi, whereas enhanced BACE1 levels in the early endosomes and the lysosomes. The reduction of BACE1 levels induced by knockdown or inhibition of SMS1 is prevented by inhibition of lysosomes. Therefore, knockdown or inhibition of SMS1 promotes lysosomal degradation of BACE1 via modulating the intracellular trafficking of BACE1. Knockdown of SMS1 attenuates AD-like pathology through promoting lysosomal degradation of BACE1.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácido Aspártico Endopeptidases
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Precursor de Proteína beta-Amiloide
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Transferases (Outros Grupos de Fosfato Substituídos)
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Secretases da Proteína Precursora do Amiloide
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Presenilina-1
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Doença de Alzheimer
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Lisossomos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article