ReferenceID 1601
Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway
Autophagy
Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-beta (Abeta) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Abet
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- Reference Id
- 1601
- Evidence Id
- 18191
- Core Evidence Id
- 18191
- Source Reference Id
- 3206
- Herb2 Reference Id
- HBREF004003
- Subject Paper Key
- HBIN021703_33404280
- Pubmed Id
- 33404280
- Doi
- 10.1080/15548627.2021.1872187
- Paper Title
- Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway
- Paper Abstract
- Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-beta (Abeta) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Abeta 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 Abeta. Failure of autophagic clearance of Abeta is currently acknowledged as a contributing factor to increased accumulation of Abeta 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 Abeta 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 Abeta 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.Abbreviations: Abeta: amyloid-beta; ABCB1/P-gp/P-glycoprotein: ATP-binding cassette, subfamily B (MDR/TAP), member 1; AD: Alzheimer disease; AMPK/PRKAA: AMP-activated protein kinase; APP: amyloid beta (A4) precursor protein; ATG: autophagy related; BBB: blood-brain barrier; BECN1: beclin 1, autophagy related; CAMKK2/CaMKKbeta: calcium/calmodulin-dependent protein kinase kinase 2, beta; CSE: Crocus sativus extract; CTSB: cathepsin B; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GFAP: glial fibrillary acidic protein; GSK3B/GSK3beta: glycogen synthase kinase 3 beta; Kp: brain partition coefficient; LRP1: low density lipoprotein receptor-related protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule-associated protein 2; MAPK/ERK: mitogen-activated protein kinase; MAPT/tau: microtubule-associated protein tau; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTOR: mechanistic target of rapamycin kinase; MWM: Morris water maze; NFKB/NF-kappaB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NMDA: N-methyl-d-aspartic acid; RPTOR: regulatory associated protein of MTOR; RPS6KB1/p70S6K: ribosomal protein S6 kinase 1; SQSTM1: sequestosome 1; SRB: sulforhodamine B; STK11/LKB1: serine/threonine kinase 11; TFEB: transcription factor EB; TSC2: TSC complex subunit 2; ULK1: unc-51 like kinase 1.
- Journal
- Autophagy
- Publish Year
- 2021
- Experiment Subject
- mouse; n9 cells; n9 microglial
- Experiment Type
- Cell Experiment
- Phenotype Related
- Alzheimer Disease
- Paper Title Cn
- Paper Title En
- Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway
- Bilingual Status
- semi_complete