DHCR24 deficiency causes AD-like pathology and cognitive decline via the cGAS-STING signaling pathway

Schematic summary of the molecular mechanism underlying DHCR24 knockdown-induced cognitive dysfunction mediated by the cGAS-STING signaling pathway. • DHCR24 suppression induces brain cholesterol deficiency. • Brain cholesterol deficiency drives AD pathogenesis, inducing cognitive deficits, tau pathology, neuroinflammation, and synaptic dysfunction in C57BL/6 mice. • Brain cholesterol deficiency links to AD-like pathology via cGAS-STING signaling pathway activation. • STING inhibition attenuates DHCR24 deficiency-induced AD-like pathology, revealing a promising therapeutic strategy for AD. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles accompanied by cognitive decline and memory impairment. Emerging evidence indicates that the dysregulation of cerebral cholesterol metabolism might be involved in the pathogenesis of neurodegenerative diseases. Among the regulators of brain cholesterol homeostasis, 24-dehydrocholesterol reductase (DHCR24) plays a pivotal role in regulating brain cholesterol biosynthesis and level. Although cholesterol dyshomeostasis has been increasingly implicated in AD pathogenesis, the potential molecular mechanism between brain cholesterol deficiency and AD-associated neuropathology remains unclear. In this study, we showed that brain cholesterol deficiency, caused by genetic suppression of DHCR24 , contributed to AD-associated neuropathology and cognitive decline in C57BL/6 mice. Mechanistically, DHCR24 knockdown triggered the upregulation of cGAS and STING expression and enhanced phosphorylation of TBK1 and IRF3 in the hippocampus, indicating activation of the cGAS‒STING signaling pathway. Microglial STING activation with increased type I interferon (IFN-Is) and IFN-stimulated cytokines suggests the initiation of neuroinflammatory cascades. Furthermore, DHCR24 deficiency disrupted synaptic integrity and promoted tau hyperphosphorylation in the hippocampus. Pharmacological inhibition of STING using C-176 effectively attenuated DHCR24 -knockdown-induced AD-like pathologies and cognitive impairments. These findings demonstrate that brain cholesterol deficiency caused by DHCR24 knockdown could lead to AD-like pathologies, including cognitive decline, tau pathology, neuroinflammation and synaptic injury, partly via activation of cGAS-STING signaling pathway in mice. Our research confirms the molecular mechanism of brain cholesterol deficiency in AD pathogenesis and highlights the therapeutic potential of targeting cGAS-STING signaling pathway.