10.6084/m9.figshare.7872008.v3 Abubakar Wani Abubakar Wani Mehak Gupta Mehak Gupta Masroor Ahmad Masroor Ahmad Aabid M. Shah Aabid M. Shah Aitizaz Ul Ahsan Aitizaz Ul Ahsan Parvaiz H Qazi Parvaiz H Qazi Fayaz Malik Fayaz Malik Gurdarshan Singh Gurdarshan Singh Parduman R. Sharma Parduman R. Sharma Amal Kaddoumi Amal Kaddoumi Sandip B. Bharate Sandip B. Bharate Ram A. Vishwakarma Ram A. Vishwakarma Ajay Kumar Ajay Kumar Alborixin clears amyloid-β by inducing autophagy through PTEN-mediated inhibition of the AKT pathway Taylor & Francis Group 2019 Alborixin alzheimer disease amyloid beta autophagy microglial cells primary neuronal cells 2019-08-17 07:55:05 Journal contribution https://tandf.figshare.com/articles/journal_contribution/Alborixin_clears_amyloid-_by_inducing_autophagy_through_PTEN-mediated_inhibition_of_the_AKT_pathway/7872008 <p>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 <i>PTEN</i> and consistent, constitutive activation of <i>AKT</i> 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.</p> <p>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</p>