Restoring Aquaporin-4 alleviates molecular and motor phenotypes in zQ175 mouse model of Huntington disease

A study investigated whether restoring aquaporin-4 (AQP4) could alleviate the molecular and motor symptoms of the zQ175 mouse model of Huntington disease (HD). Huntington disease is characterized by the buildup of mutant huntingtin protein, neurodegeneration, and motor dysfunction. Researchers postulated that impaired glymphatic function and loss of AQP4 polarization might contribute to the disease pathogenesis.

The study focused on heterozygous zQ175 knock-in mice, which were injected with a single retro-orbital injection of AAV9-Phil.eB encoding AQP4 (M1 isoform) when they were 2 months old. Glymphatic transport was evaluated by intracisternal injection of fluorescent BSA 647, and the parenchymal influx and drainage to the deep cervical lymph nodes were measured.

The researchers assessed perivascular AQP4 localization, mHTT aggregation, gliosis, DARPP32 immunoreactivity, CSF neurofilament light chain and total Tau, structural brain volumes using 11.7T MRI, and motor behavior over a period of 12 months. The results showed that AAV9-Phil.eB-AQP4 led to widespread brain expression and restored perivascular AQP4 localization in the striatum and cortex of the zQ175 mice.

Restoring AQP4 overexpression significantly increased glymphatic tracer influx into the brain parenchyma and BSA-647 drainage to the deep cervical lymph nodes. By the 12-month mark, AQP4 restoration led to a reduction in CSF NfL and total Tau concentrations, a decrease in mHTT aggregate number and size, and a reduction in striatal Iba1 positive microglia and GFAP-positive astrocytes.