Journal
EXPERIMENTAL NEUROLOGY
Volume 311, Issue -, Pages 67-79Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2018.09.012
Keywords
BACE1; Sphingomyelin; Amyloid-beta; Lysosomal degradation; Alzheimer's disease; Lipids
Categories
Funding
- National Natural Science Foundation of China [81870897, 81671111, 81601111]
- Natural Science Foundation of Jiangsu Province, China [BK20181436, BK20150347]
- Foundation of higher Education of Jiangsu Province, China [15JKB310022]
- Priority Academic Program Development of Jiangsu Higher Education Institution, China (PAPD)
- Suzhou Clinical Research Center of Neurological Disease, China [Szzx201503]
- Jiangsu Provincial Medical Key Discipline Project, China [ZDXKB2016022]
- Jiangsu Provincial Special Program of Medical Science, China [BL2014042]
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, China [BM2013003]
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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 beta-site APP cleaving enzyme 1 (BACE1), a rate limiting enzyme in amyloid-beta (A beta) 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 A beta 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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