Alborixin clears amyloid-β by inducing autophagy through PTEN-mediated inhibition of the AKT pathway
| Autor: | Sandip B. Bharate, Masroor Ahmad, Parduman R. Sharma, Abubakar Wani, Mehak Gupta, Ram A. Vishwakarma, Gurdarshan Singh, Fayaz Malik, Aabid Manzoor Shah, Ajay Kumar, Amal Kaddoumi, Parvaiz H. Qazi, Aitizaz Ul Ahsan |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Amyloid beta ATG5 Biology Mice 03 medical and health sciences Sequestosome 1 Autophagy Animals Humans education Molecular Biology Mechanistic target of rapamycin Cells Cultured PI3K/AKT/mTOR pathway Pyrans education.field_of_study Amyloid beta-Peptides 030102 biochemistry & molecular biology PTEN Phosphohydrolase Cell Biology BECN1 Embryo Mammalian Cell biology Mice Inbred C57BL 030104 developmental biology Proteolysis biology.protein Proto-Oncogene Proteins c-akt MAP1LC3B Research Paper Signal Transduction |
| DOI: | 10.6084/m9.figshare.7872008.v3 |
| Popis: | Imbalance in production and clearance of amyloid beta (Aβ) is the primary reason for its deposition in Alzheimer disease. Macroautophagy/autophagy is one of the important mechanisms for clearance of both intracellular and extracellular Aβ. Here, through screening, we identified alborixin, an ionophore, as a potent inducer of autophagy. We found that autophagy induced by alborixin substantially cleared Aβ in microglia and primary neuronal cells. Induction of autophagy was accompanied by up regulation of autophagy proteins BECN1/Beclin 1, ATG5, ATG7 and increased lysosomal activities. Autophagy induced by alborixin was associated with inhibition of the phosphoinositide 3-kinase (PI3K)-AKT pathway. A knock down of PTEN and consistent, constitutive activation of AKT inhibited alborixin-induced autophagy and consequent clearance of Aβ. Furthermore, clearance of Aβ by alborixin led to significant reduction of Aβ-mediated cytotoxicity in primary neurons and differentiated N2a cells. Thus, our findings put forward alborixin as a potential anti-Alzheimer therapeutic lead. Abbreviations: Aβ: amyloid beta; ALB: alborixin; ATG: autophagy-related; BECN1: beclin 1; DAPI: 4, 6-diamidino-2-phenylindole; DCFH-DA: 2,7-dichlorodihydrofluorescein diacetate; fAβ: fibrillary form of amyloid beta; GFAP: glial fibrillary acidic protein; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule-associated protein 2; MTOR: mechanistic target of rapamycin kinase; PTEN: phosphatase and tensin homolog; ROS: reactive oxygen species; SQSTM1: sequestosome 1; TMRE: tetramethylrhodamine, ethyl ester |
| Databáze: | OpenAIRE |
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