Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease

Xinwen Zhang, Rihua Wang, Di Hu, Xiaoyan Sun, Hisashi Fujioka, Kathleen Lundberg, Ernest R. Chan, Quanqiu Wang, Rong Xu, Margaret E. Flanagan, Andrew A. Pieper, Xin Qi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


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.

Original languageEnglish (US)
Article numbereabb8680
JournalScience Advances
Issue number49
StatePublished - Dec 4 2020

ASJC Scopus subject areas

  • General


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