Magnetic resonance imaging and transcriptome-proteome integration analysis demonstrate improved disease-outcome in the cuprizone mouse model following AAV-mediated delivery of A Proliferation Inducing Ligand

ABSTRACT: A Proliferation Inducing Ligand (APRIL) is a member of the tumour necrosis factor (TNF) superfamily and has recently been shown to modulate pro-inflammatory astrocyte responses, as well as to ameliorate disease outcome in the experimental autoimmune encephalomyelitis mouse model for multiple sclerosis (MS). In this new study, an unbiased proteomic analysis first confirmed that adeno-associated virus (AAV)-mediated delivery of APRIL was able to rescue immune-stimulated murine iPSC-derived neurospheroids from detrimental cell death and neurodegenerative processes. Next, we investigated whether AAV-mediated secretion of APRIL by cortical neurons could influence cuprizone-induced neuro-inflammation and/or demyelination in the splenium of the corpus callosum. Applying both T2 and diffusion-weighted magnetic resonance imaging (MRI), with subsequent histological confirmation, our results indicated that cortical secretion of APRIL is able to reduce neuro-inflammatory and demyelinating events in the splenium. To further document the beneficial effect of APRIL, a transcriptome-proteome integration study for the splenium revealed the activation of cellular pathways associated with alternative immune cell polarisation, cell survival and neuroregeneration. Lastly, even though our MRI and transcriptome-proteome integration study for the cortical AAV injection site noted a local activation of cellular pathways associated with inflammation, these events were not associated with major abnormalities in histological appearance. Concluding, our findings highlight that APRIL has strong anti-inflammatory and neuroprotective effects in the CNS which may have the potential to improve MS-like disease outcome.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Federica Di Marco  

LAB HEAD: Peter Ponsaerts

PROVIDER: PXD056011 | Pride | 2025-11-10

REPOSITORIES: Pride