As the name might suggest, aquaporin proteins facilitate the transfer of water molecules across cell membranes. This is important in a broad range of contexts, such as the operation of the blood-brain barrier that wraps blood vessels that pass through the brain, and in the drainage of cerebrospinal fluid from the brain into the body. One of the paths by which cerebrospinal fluid exits the brain, carrying away metabolic waste with it, is the glymphatic system. Glymphatic vessels run parallel to the blood vessels that enter and exit the brain. Research is making it increasingly apparent that drainage of cerebrospinal fluid is vital to the health of the brain. Unfortunately this drainage becomes progressively ever more impaired with advancing age, and this is thought to contribute to the buildup of protein aggregates and other forms of metabolic waste in the brain, contributing to inflammation, cell dysfunction, and neurodegenerative conditions.
In today's open access paper, researchers build on past work on the manipulation of aquaporin 4 (AQP4) activity in the glymphatic system. A small molecule compound TGN-073 increases the activity of AQP4 via a mechanism that isn't understood, but may involve altering the structure of AQP4 to broaden the size of the pores it creates in the cell membrane. Other work has shown that different isoforms and thus structures of AQP4 are more effective than the usual version, for example. Here, researchers show that this increased AQP4 activity does in fact help to reduce neurodegenerative pathology in mice, supporting the importance of failing cerebrospinal fluid drainage in the development and progression of neurodegenerative conditions.
The glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.
Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.
PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.
Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.
View the full article at FightAging
