| First Author | Zhang X | Year | 2020 |
| Journal | Sci Adv | Volume | 6 |
| Issue | 49 | PubMed ID | 33277246 |
| Mgi Jnum | J:299756 | Mgi Id | MGI:6490031 |
| Doi | 10.1126/sciadv.abb8680 | Citation | Zhang X, et al. (2020) Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer's disease. Sci Adv 6(49) |
| abstractText | Myelin degeneration and white matter loss resulting from oligodendrocyte (OL) death are early events in Alzheimer's disease (AD) that lead to cognitive deficits; however, the underlying mechanism remains unknown. Here, we find that mature OLs in both AD patients and an AD mouse model undergo NLR family pyrin domain containing 3 (NLRP3)-dependent Gasdermin D-associated inflammatory injury, concomitant with demyelination and axonal degeneration. The mature OL-specific knockdown of dynamin-related protein 1 (Drp1; a mitochondrial fission guanosine triphosphatase) abolishes NLRP3 inflammasome activation, corrects myelin loss, and improves cognitive ability in AD mice. Drp1 hyperactivation in mature OLs induces a glycolytic defect in AD models by inhibiting hexokinase 1 (HK1; a mitochondrial enzyme that initiates glycolysis), which triggers NLRP3-associated inflammation. These findings suggest that OL glycolytic deficiency plays a causal role in AD development. The Drp1-HK1-NLRP3 signaling axis may be a key mechanism and therapeutic target for white matter degeneration in AD. |
