A systemic cell stress signal confers neuronal resilience toward oxidative stress in a Hedgehog-dependent manner

Chung, Kyung Min; Kim, Hyunha; Roque, Cláudio Gouveia; McCurdy, Ethan P.; Nguyen, Trang; Siegelin, Markus D.; Hwang, Jee-Yeon; Hengst, Ulrich

doi:10.1016/j.celrep.2022.111488

Cited by 11 publications

(3 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the brain, inducing UPR in astrocytes impaired their synaptogenic function in vitro and induced non-cell-autonomous neurodegeneration in a model of Prion disease 106 . However, ISR induced by oxidative stress in neurons increases the resistance of naïve neurons to oxidative stress 107 . Thus, in the context of AD, the potential interplay between non-cell-autonomous stress signaling from various cell types remains to be untangled.…”

Section: Discussionmentioning

confidence: 99%

“…Primary cultures of cortical neurons were isolated from mouse embryos on embryonic day E16 as described previously 107 with slight modifications. Briefly, embryonic cortices were digested with 0.025% trypsin-EDTA for 15 min at 37°C, followed by incubation with NM10 medium (DMEM with 10% fetal bovine serum) for 5 min at room temperature.…”

Section: Primary Neuron Culturesmentioning

confidence: 99%

See 1 more Smart Citation

Integrated stress response associated with dark microglia promotes microglial lipogenesis and contributes to neurodegeneration

Flury,

Aljayousi,

Aziz

et al. 2024

Preprint

View full text Add to dashboard Cite

Microglia, the brain′s primary resident immune cells, are a heterogeneous population and can assume phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimer′s disease (AD), where microglia are a leading causal cell type, microglia subsets with protective functions have been well characterized. Yet, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we identify a neurodegenerative microglia phenotype that is characterized by a conserved stress signaling pathway, the integrated stress response (ISR). Using mouse models to activate or inhibit ISR in microglia, we show that ISR underlies the ultrastructurally distinct ″dark″ microglia subset linked to pathological synapse loss. Inducing microglial ISR in murine AD models exacerbates neurodegenerative pathologies, such as Tau pathology and synapse loss. Conversely, inhibiting microglial ISR in AD models ameliorates these pathologies. Mechanistically, we present evidence that ISR promotes the secretion of toxic long-chain lipids that impair neuron and oligodendrocyte homeostasis in vitro. Accordingly, small molecule-based inhibition of lipid synthesis in AD models ameliorates synapse loss. Our results demonstrate that activation of ISR within microglia represents a novel pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of long-chain lipids from ISR-activated microglia.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Primary Neuron Culturesmentioning

confidence: 99%

Integrated stress response associated with dark microglia promotes microglial lipogenesis and contributes to neurodegeneration

Flury,

Aljayousi,

Aziz

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The 4-VO model leads to delayed and selective neuronal death and cognitive impairment. 1 , 11 To measure cell viability and cognitive function, histological assays and behavioral tests were performed at 7 days after 4-VO ( Figure 5 A). The number of neurons was significantly reduced in the hippocampal CA1 pyramidal layer after 4-VO, but not in the CA3 or dentate gyrus region as shown by Toluidine Blue staining.…”

Section: Expected Outcomesmentioning

confidence: 99%

Protocol for establishing a global ischemia model using a 4-vessel occlusion in rats

Kim,

Urquhart,

Pontarelli

et al. 2023

STAR Protocols

Self Cite

View full text Add to dashboard Cite

Regulatory mechanisms of the cAMP-responsive element binding protein 3 (CREB3) family in cancers

Yuxiong,

Faping,

Bin

et al. 2023

Biomedicine & Pharmacotherapy

View full text Add to dashboard Cite

A systemic cell stress signal confers neuronal resilience toward oxidative stress in a Hedgehog-dependent manner

Cited by 11 publications

References 55 publications

Integrated stress response associated with dark microglia promotes microglial lipogenesis and contributes to neurodegeneration

Integrated stress response associated with dark microglia promotes microglial lipogenesis and contributes to neurodegeneration

Protocol for establishing a global ischemia model using a 4-vessel occlusion in rats

Regulatory mechanisms of the cAMP-responsive element binding protein 3 (CREB3) family in cancers

Contact Info

Product

Resources

About