Endothelial TFEB signaling-mediated autophagic disturbance initiates microglial activation and cognitive dysfunction.

Autor:	Lu Y; Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China., Chen X; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China., Liu X; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China., Shi Y; Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China., Wei Z; Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China., Feng L; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China., Jiang Q; Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China., Ye W; Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China., Sasaki T; Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan., Fukunaga K; Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan., Ji Y; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China.; Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China., Han F; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China.; Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.; Institute of Brain Science, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China., Lu YM; Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.; Institute of Brain Science, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Jazyk:	angličtina
Zdroj:	Autophagy [Autophagy] 2023 Jun; Vol. 19 (6), pp. 1803-1820. Date of Electronic Publication: 2023 Jan 01.
DOI:	10.1080/15548627.2022.2162244
Abstrakt:	Cognitive impairment caused by systemic chemotherapy is a critical question that perplexes the effective implementation of clinical treatment, but related molecular events are poorly understood. Herein, we show that bortezomib exposure leads to microglia activation and cognitive impairment, this occurs along with decreased nuclear translocation of TFEB (transcription factor EB), which is linked to macroautophagy/autophagy disorder, STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL23A (interleukin 23 subunit alpha) expression. Pharmacological enhancement of TFEB nuclear translocation by digoxin restores lysosomal function and reduces STAT3-dependent endothelial IL23A secretion. As a consequence, we found that brain endothelial-specific ablation of Il23a ameliorated both microglia activation and cognitive dysfunction. Thus, the endothelial TFEB-STAT3-IL23A axis in the brain represents a critical cellular event for initiating bortezomib-mediated aberrant microglial activation and synapse engulfment. Our results suggest the reversal of TFEB nuclear translocation may provide a novel therapeutic approach to prevent symptoms of cognitive dysfunction during clinical use of bortezomib. Abbreviations: AAV: adeno-associated virus; BBB: blood-brain barrier; BTZ: bortezomib; DG: digoxin; DGs: dentate gyrus; DLG4/PSD95: discs large MAGUK scaffold protein 4; HBMECs: human brain microvascular endothelial cells; HP: hippocampus; IL23A: interleukin 23 subunit alpha; MBVECs: mouse brain vascular endothelial cells; mPFC: medial prefrontal cortex; NORT: novel object recognition test; OLT: object location test; PLX5622: 6-fluoro-N-([5-fluoro-2-methoxypyridin-3-yl]methyl)-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3- yl)methyl; PPP3/calcineurin: protein phosphatase 3; SBEs: STAT3 binding elements; shRNA: small hairpin RNA; SLC17A7/VGLUT1: solute carrier family 17 member 7; SLC32A1/VGAT: solute carrier family 32 member 1; STAT3: signal transducer and activator of transcription 3, TFEB: transcription factor EB; Ub: ubiquitin.
Databáze:	MEDLINE
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