Crocetin promotes clearance of amyloid-beta by inducing autophagy via the STK11/LKB1-mediated AMPK pathway

Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-beta (A beta) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of A beta largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a lysosomal degradative process, which plays an important role in the clearance of A beta. Failure of autophagic clearance of A beta is currently acknowledged as a contributing factor to increased accumulation of A beta in AD brains. In this study, we have identified crocetin, a pharmacologically active constituent from the flower stigmas of Crocus sativus, as a potential inducer of autophagy in AD. In the cellular model, crocetin induced autophagy in N9 microglial and primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein kinase (AMPK) pathway activation. Autophagy induction by crocetin significantly increased A beta clearance in N9 cells. Moreover, crocetin crossed the blood-brain barrier and induced autophagy in the brains' hippocampi of wild-type male C57BL/6 mice. Further studies in transgenic male 5XFAD mice, as a model of AD, revealed that one-month treatment with crocetin significantly reduced A beta levels and neuroinflammation in the mice brains and improved memory function by inducing autophagy that was mediated by AMPK pathway activation. Our findings support further development of crocetin as a pharmacological inducer of autophagy to prevent, slow down progression, and/or treat AD.