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.