Presenter of 1 Presentation
CHRONIC PHARMACOLOGICAL INHIBITION OF GLYMPHATIC FUNCTION EXACERBATES PROPAGATION OF TAU PATHOLOGY IN AN ANIMAL MODEL
Abstract
Aims
The glymphatic system describes the exchange of peri-arterial cerebrospinal fluid (CSF) with interstitial fluid in the parenchymal extracellular space, and peri-venous clearance out of the brain. Facilitated by astrocytic aquaporin-4 channels, this pathway has been shown to effectively clear proteins prone to propagation and aggregation in neurodegenerative diseases, such as amyloid-β, tau, and α-synuclein. Here, we tested proof-of-principle, that modulation of glymphatic function affects propagation of tau pathology in an animal model of such pathological aetiology.
Methods
Tau propagation was initiated in young (2 m.o.) Thy1-hTau.P301S mice (P301S mice), by injection of aged P301S mouse brain homogenate, into the hippocampus and overlying cortex. Animals subsequently received chronic treatment with the pharmacological aquaporin-4 inhibitor, TGN-020 (50mg/kg, i.p., 3 times/week) or vehicle for 10 weeks. Behavioural performance was accessed at baseline, 2, 4 and 10 weeks post-injection, after which in vivo structural brain MRI scans were acquired, and CSF and brains were collected for quantification of tau propagation, aggregation and resultant neurodegeneration following chronic impairment of glymphatic function.
Results
Mice chronically treated with TGN-020 exhibited exacerbated outcomes in hippocampal dependent cognitive memory tasks compared to vehicle treated controls. This was accompanied by intensified atrophy in treated brains, and a greater extent of tau aggregation and neurodegeneration following chronic drug treatment.
Conclusions
These data suggest that modulation of the function of the water channel aquaporin-4, and by extension the function of the glymphatic system, is capable of altering the extent to which tau is able to propagate throughout the brain.