Aquaporin-4 deficiency induced white matter injury via upregulated complement component 3 in cerebral small vessel disease

Jan 22, 2026Journal of neuroinflammation

Lack of Aquaporin-4 may cause white matter damage through increased complement component 3 in small blood vessel brain disease

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Abstract

Four single-nucleotide polymorphisms (SNPs) were significantly associated with the presence of (CSVD).

The SNP rs335929 was correlated with reduced mRNA expression in the context of CSVD.
Mice exhibited decreased fractional anisotropy values and increased demyelination in the corpus callosum under BCAS conditions.
Intraventricular delivery of AAV2/9 vectors attenuated BCAS-induced white matter injury without significant differences between treatment groups.
RNA sequencing revealed upregulation of inflammatory responses and complement cascades in the corpus callosum of mice with deficiency.
Treatment with a C3a receptor antagonist improved myelin integrity and reduced loss of myelin basic protein (MBP) in the BCAS model.

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BACKGROUND: (CSVD) is the most common neurological disorder associated with a high incidence of stroke and dementia. For the heterogeneity of the pathogenesis, effective preventive and therapeutic strategies remain limited. Reduced (AQP4) was reported in the development of CSVD, while its role and mechanisms have not been fully elucidated.

METHODS: We employed logistic regression analysis to assess the association betweengene single-nucleotide polymorphisms (SNPs) and CSVD presence. The functional impact of SNP mutations ongene was evaluated using a Luciferase assay. Subsequently,mice were subjected to bilateral carotid artery stenosis (BCAS) surgery to detect the CSVD phenotype of Aqp4 reduction.andmice in the Sham and BCAS groups were subjected to MRI, histological examinations, and behavioural tests. AAV2/9--and AAV2/9--were used to investigateexpression and translocation ability after BCAS. Furthermore, RNA-sequencing was performed on the corpus callosum (CC) andastrocytes to identify transcriptional changes associated with Aqp4 deficiency. AQP4AQP4Aqp4Aqp4Aqp4Gfap AQP4Gfap AQP4Aqp4Aqp4 −/− +/+ −/− M1 7×cMyc−Kras −/−

RESULTS: We identified four SNPs (rs335929, rs335930, rs335931 and rs455671) were significantly associated with CSVD presence. Among these, rs335929 variant was correlated with reducedmRNA expression. Compared withmice, fractional anisotropy values were decreased in the Sham and BCAS groups inmice. Under BCAS conditions,mice exhibited more severe demyelination and myelin density in the CC. Intraventricular delivery of AAV2/9--and AAV2/9--attenuated BCAS-induced white matter injury and cognitive function, no significant differences were observed between the two AAV treatment groups. RNA sequencing analysis indicated upregulation of inflammatory responses and complement cascades in the CC ofmice. (C3) mRNA was notably elevated in astrocytes isolated frommice. Treatment with a C3a receptor antagonist inmice improved myelin integrity and reduced MBP loss following BCAS. AQP4Aqp4Aqp4Aqp4Gfap AQP4Gfap AQP4Aqp4Aqp4Aqp4 +/+ −/− −/− M1 7×cMyc−Kras −/− −/− − −/

CONCLUSION: Reducedexpression was associated with CSVD presence in clinical studies. Experimentally,deficiency has been shown to exacerbate white matter injury, that effect may be mediated by upregulation ofmRNA in-deficient astrocytes. Targeting C3 activation may represent a promising strategy to mitigate AQP4 loss-induced white matter injury in CSVD. AQP4Aqp4C3Aqp4

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03688-w.

Key numbers

1.14

SNP Association

Odds ratio for rs335929 SNP associated with presence.

0.39

Fractional Anisotropy (FA) Decrease

Mean FA value in -deficient mice post-surgery.

484

mRNA Elevation

Number of genes upregulated in astrocytes from -deficient mice.

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Aquaporin-4 deficiency induced white matter injury via upregulated complement component 3 in cerebral small vessel disease

Abstract

Key numbers

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