TGN-073 reduced tau pathology in mice by activating the AQP4 water channel

TGN-073 reduced tau pathology in mice by activating the AQP4 water channel

In PS19 mice with tau pathology, the AQP4 activator TGN-073 increased the influx of an MRI tracer from the cerebrospinal fluid. The brain tissue contained less pathological tau, neurons were better preserved, and gliosis, the response of support cells to injury, was reduced. These effects were absent in mice lacking AQP4. The paper was published in Molecular Neurodegeneration on July 18.

PS19 is a mouse line that expresses mutant human tau protein. The protein forms aggregates inside neurons, damages them, and reproduces some features of tauopathy. The authors administered TGN-073, a compound that activates the AQP4 water channel, chronically to these mice.

The brain has no separate pipe for clearing proteins. Cerebrospinal fluid moves along blood vessels, exchanges with the fluid between cells, and carries away dissolved substances. This pathway is called the glymphatic system. AQP4 is located in astrocyte processes surrounding blood vessels and directs water flow across their membranes. The authors therefore measured both the total amount of AQP4 in the brain and how densely the channel was concentrated around blood vessels.

Fluid exchange in PS19 mice began to weaken before the disease reached an advanced stage and deteriorated further with age. After TGN-073 treatment, more MRI tracer entered the brain from the cerebrospinal fluid. The tissue contained less pathological tau, neurons were better preserved, and gliosis was reduced. At the same time, tau levels increased in the cerebrospinal fluid, while AQP4 again became more densely concentrated around blood vessels.

The authors then repeated the experiment in PS19 mice lacking AQP4. TGN-073 no longer increased tracer influx or reduced tau pathology, gliosis, or neuronal loss. In this model, all observed effects of TGN-073 required AQP4.

The connection between TGN-073 and fluid movement had prior support. A 2023 study found that MRI also showed a broader distribution of contrast after healthy rats received this compound. The new paper extends this work to a tauopathy model. In this model, the same target is associated with fluid movement, tau accumulation, and neuronal preservation.

For tauopathy, these are two distinct intervention strategies: reducing tau production or changing the fluid movement that removes tau from tissue. In chimeric mice, AAV vectors have already been delivered through cerebrospinal fluid flow to carry genetic cargo to human glial cells. Meanwhile, VY1706 is intended to reduce tau production in the brain with a single viral injection. In the PS19 model, TGN-073 acted through a different pathway involving AQP4 and fluid flow around blood vessels.