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INVESTIGATING GLYMPHATIC FUNCTION DURING EARLY TAU PATHOLOGY USING DYNAMIC CONTRAST-ENHANCED MRI

      Background

      The glymphatic system describes the cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange pathway that facilitates efficient clearance of solutes and waste from the brain [1]. Because waste solutes, such as amyloid-β and tau, can depend on the glymphatic pathway for clearance, we proposed that failure of this clearance system may contribute to tau accumulation and Alzheimer’s disease (AD) progression. Using dynamic contrast-enhanced MRI, we visualised CSF-ISF exchange across the mouse brain following subarachnoid contrast agent administration. We previously provided evidence that glymphatic clearance is impaired during the later stages of tauopathy[2]. Here we investigate glymphatic function in the early stages prior to the onset of mature tangle formation and neurodegeneration to identify the stage at which glymphatic clearance becomes impaired during the pathological tau accumulation in the mouse brain.

      Methods

      Glymphatic clearance in rTg4510 and litter-matched wildtype mice at 2.5 months and 5 months of age was captured using contrast-enhanced MRI. Gadolinium was infused intracisternally and its whole brain distribution was dynamically imaged in real-time using T1-weighted MRI. Histological assessment of astrocytes surrounding blood vessels and quantification of aquaporin-4 expression was also performed, as derangement of this water channel in glymphatic impairment was previously found in rTg4510 aged mice [2].

      Results

      Glymphatic CSF-ISF exchange was not impaired in 2.5 month old rTg4510 mice prior to mature tangle formation, compared to wildtype animals. However, there was a marginal elevation of CSF-ISF exchange at 5 months of age in rTg4510 mice with the presence of mature tangles.

      Conclusions

      In the context of our previous findings at 8.5 months in rTg4510 mice [2], impaired glymphatic clearance from the brain is dependent on the onset of neurodegeneration and is not influenced by intracellular tangle formation. This suggests that glymphatic impairment is a consequence rather than a contributor to tau pathology in this tauopathy model. This is in line with elevated CSF tau in AD patients. Changes in expression and polarisation profiles of astrocytic aquaporin-4 may highlight possible roles of this protein in preceding impaired glymphatics in this mouse model. References: [1] Iliff, J.J. et al. (2012), SciTransMed, 4(147):p.147. [2] Harrison, I.F. et al., (2015), Alz&Dementia, Supplement IC-P-160. 11 (7):p.P107.