Neuroinflammation in an optimized model of lysophosphatidic acid (LPA)-induced post-hemorrhagic hydrocephalus

TL;DR

This study explores how neuroinflammation contributes to post-hemorrhagic hydrocephalus in a mouse model and identifies microglial pathways as potential treatment targets.

Contribution

The study introduces an optimized mouse model of PHH and identifies microglial pathways as novel therapeutic targets.

Findings

Transcriptomic and proteomic features of PHH in mice mirror those in human disease.

Pharmacological microglia depletion reduces ventriculomegaly in PHH.

Microglial and neurovascular elements are implicated in PHH progression.

Abstract

Post-hemorrhagic hydrocephalus (PHH) is a neurological disease that primarily affects premature infants and involves infiltration of blood into the brain’s ventricles followed by excessive accumulation of cerebrospinal fluid (CSF), leading to ventricular enlargement and increased intracranial pressure. The precise mechanisms driving PHH development and persistence are incompletely understood and lack disease-modifying treatments. Using a mouse model of PHH, we have identified transcriptomic, proteomic, and cellular features of PHH involving neuroimmune and neurovascular alterations recapitulating those reported in human disease. Improvement upon a lysophosphatidic acid (LPA)-induced PHH mouse model was combined with unbiased proteomic and single-nucleus transcriptomics that identified microglial molecular pathways propagating PHH. Pharmacological depletion of microglia in vivo significantly reduced PHH-associated ventriculomegaly. These data identify microglial and neurovascular elements in the development of PHH, implicating them as other potentially tractable therapeutic targets beyond LPA receptors, towards developing medical treatments for PHH.

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