Alborixin clears amyloid-β by inducing autophagy through PTEN-mediated inhibition of the AKT pathway.

Abstract

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.

• Authors: Abubakar Wani, Mehak Gupta, Masroor Ahmad, Aabid M Shah, Aitizaz Ul Ahsan, Parvaiz H Qazi, Fayaz Malik, Gurdarshan Singh, Parduman R Sharma, Amal Kaddoumi, Sandip B Bharate, Ram A Vishwakarma, Ajay Kumar
• Journal: Autophagy (Autophagy) Vol. 15 Issue 10 Pg. 1810-1828 (10 2019) ISSN: 1554-8635 [Electronic] United States
• PMID: 30894052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Pyrans
• alborixin
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Amyloid beta-Peptides (drug effects, metabolism)
• Animals
• Autophagy (drug effects, physiology)
• Cells, Cultured
• Embryo, Mammalian
• Humans
• Mice
• Mice, Inbred C57BL
• PTEN Phosphohydrolase (genetics, physiology)
• Proteolysis (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrans (pharmacology)
• Signal Transduction (drug effects, genetics)