@article{7ba64b1dc7b24d9b8bda52061202d748,
title = "Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer{\textquoteright}s disease",
abstract = "Myelin degeneration and white matter loss resulting from oligodendrocyte (OL) death are early events in Alzheimer{\textquoteright}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.",
author = "Xinwen Zhang and Rihua Wang and Di Hu and Xiaoyan Sun and Hisashi Fujioka and Kathleen Lundberg and Chan, {Ernest R.} and Quanqiu Wang and Rong Xu and Flanagan, {Margaret E.} and Pieper, {Andrew A.} and Xin Qi",
note = "Funding Information: This study was supported by a pilot grant from the Department of Physiology and Biophysics, Case Western Reserve University, and a research grant from Dr. Ralph and Marian Falk Medical Research Foundation Transformative Award to X.Q. The postmortem brain tissues were provided by the Neuropathology Core of Northwestern University (NIH P30 AG013854 24) and the NIH NeuroBioBank. The study with the mouse genotypes was supported by a P30 core grant for vision research (NIH 5P30EY011373). We thank Translational Therapeutics Core of the Cleveland Alzheimer{\textquoteright}s Disease Research Center (NIH/NIA: 1 P30 AGO62428-01) for assisting in the study with human postmortem brain tissues. R.X. and Q.W. acknowledge funding from NIH National Institute of Aging (AG057557, AG061388, and AG062272). Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved;",
year = "2020",
month = dec,
day = "4",
doi = "10.1126/sciadv.abb8680",
language = "English (US)",
volume = "6",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "49",
}