Maternal immune activation leads to defective brain–blood vessels and intracerebral hemorrhages in male offspring

Rasile, Marco; Lauranzano, Eliana; Faggiani, Elisa; Ravanelli, Margherita M; Colombo, Federico; Mirabella, Filippo; Corradini, Irene; Malosio, Maria Luisa; Borreca, Antonella; Focchi, Elisa; Pozzi, Davide; Giorgino, Toni; Barajon, Isabella; Matteoli, Michela

doi:10.15252/embj.2022111192

Cited by 5 publications

(1 citation statement)

References 97 publications

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“…Our results suggest that haemorrhages may occur due to an antiviral response rather than local infection, as spike protein injections in zebrafish larvae is a non-infectious model and no correlation between bleed score and cortical spike protein levels was found in human foetal samples. Indeed, maternal immune activation has been reported to lead to neurovascular developmental defects 54 , including brain haemorrhages 55 . The effects of antiviral signalling in the developing brain can also be observed in monogenic conditions such as the type I interferonopathies.…”

Section: Discussionmentioning

confidence: 99%

25-hydroxycholesterol promotes brain endothelial dysfunction by remodelling cholesterol metabolism

Tapia,

Withers,

Zhou

et al. 2024

Preprint

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Viral infection and hypocholesterolaemia are two independent risk factors for intracerebral haemorrhage (ICH), but the molecular mechanisms leading to vascular rupture via these risk factors remain unknown. We hypothesised that the enzyme cholesterol 25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC), which modulates cholesterol metabolism during infection, may offer a mechanistic link between cholesterol dysregulation and infection during neurovascular dysfunction. We identified an upregulation of CH25H in infection-associated cerebral haemorrhage, in a SARS-CoV-2-induced zebrafish ICH model and foetal human SARS-CoV-2-associated cortical microbleeds. Using human brain endothelial cells and zebrafish ICH models, we show that 25HC promotes endothelial dysfunction and exacerbates brain bleeding. These effects involved cholesterol metabolism modulation, as cholesterol supplementation rescued these effects, while 25HC and statin treatments interacted to exacerbate dysfunction. We propose that the CH25H/25HC pathway represents an important component in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation in the context of ICH.

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Section: Discussionmentioning

confidence: 99%

25-hydroxycholesterol promotes brain endothelial dysfunction by remodelling cholesterol metabolism

Tapia,

Withers,

Zhou

et al. 2024

Preprint

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Trimester-specific effects of maternal exposure to single and mixed metals on cord serum inflammatory cytokines levels: A prospective birth cohort study

Wang

Tong

Liang

et al. 2023

Science of The Total Environment

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Dysregulation of the mTOR-FMRP pathway and synaptic plasticity in an environmental model of ASD

Hilal,

Rosina,

Pedini

et al. 2024

Mol Psychiatry

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Autism Spectrum Disorder (ASD) is caused by genetic, epigenetic, and environmental factors. Mutations in the human FMR1 gene, encoding the Fragile X Messenger Ribonucleoprotein 1 (FMRP), cause the most common monogenic form of ASD, the Fragile X Syndrome (FXS). This study explored the interaction between the FMR1 gene and a viral-like infection as an environmental insult, focusing on the impact on core autistic-like behaviors and the mGluR1/5-mTOR pathway. Pregnant heterozygous Fmr1 mouse females were exposed to maternal immune activation (MIA), by injecting the immunostimulant Poly (I:C) at the embryonic stage 12.5, simulating viral infections. Subsequently, ASD-like behaviors were analyzed in the adult offspring, at 8–10 weeks of age. MIA exposure in wild-type mice led to ASD-like behaviors in the adult offspring. These effects were specifically confined to the intrauterine infection, as immune activation at later stages, namely puberty (Pubertal Immune Activation, PIA) at post-natal day 35 or adulthood (Adult Immune Activation, AIA) at post-natal day 56, did not alter adult behavior. Importantly, combining the Fmr1 mutation with MIA exposure did not intensify core autistic-like behaviors, suggesting an occlusion effect. Mechanistically, MIA provided a strong activation of the mGluR1/5-mTOR pathway, leading to increased LTP and downregulation of FMRP specifically in the hippocampus. Finally, FMRP modulates mTOR activity via TSC2. These findings further strengthen the key role of the mGluR1/5-mTOR pathway in causing ASD-like core symptoms.

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Maternal immune activation leads to defective brain–blood vessels and intracerebral hemorrhages in male offspring

Cited by 5 publications

References 97 publications

25-hydroxycholesterol promotes brain endothelial dysfunction by remodelling cholesterol metabolism

25-hydroxycholesterol promotes brain endothelial dysfunction by remodelling cholesterol metabolism

Trimester-specific effects of maternal exposure to single and mixed metals on cord serum inflammatory cytokines levels: A prospective birth cohort study

Dysregulation of the mTOR-FMRP pathway and synaptic plasticity in an environmental model of ASD

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