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.

Mitochondria form tubular networks that undergo coordinated cycles of fission and fusion. Emerging evidence suggests that a direct yet unresolved interaction of the mechanoenzymatic GTPase dynamin-related protein 1 (Drp1) with mitochondrial outer membrane–localized cardiolipin (CL), externalized under stress conditions including mitophagy, catalyzes essential mitochondrial hyperfragmentation. Here, using a comprehensive set of structural, biophysical, and cell biological tools, we have uncovered a CL-binding motif (CBM) conserved between the Drp1 variable domain (VD) and the unrelated ADP/ATP carrier (AAC/ANT) that intercalates into the membrane core to effect specific CL interactions. CBM mutations that weaken VD–CL interactions manifestly impair Drp1-dependent fission under stress conditions and induce “donut” mitochondria formation. Importantly, VD membrane insertion and GTP-dependent conformational rearrangements mediate only transient CL nonbilayer topological forays and high local membrane constriction, indicating that Drp1–CL interactions alone are insufficient for fission. Our studies establish the structural and mechanistic bases of Drp1–CL interactions in stress-induced mitochondrial fission.

Predisposition to Alzheimer’s disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive deficits in AD transgenic mice. These findings reveal a role for ATAD3A oligomerization in AD pathogenesis and suggest ATAD3A as a potential therapeutic target for AD.