Pathological accumulation of tau and amyloid in the brains of Alzheimer’s disease (AD) patients leads to a continuum of irreversible biochemical and pathological changes and pronounced neurodegeneration. Impaired ‘glymphatic’ clearance may be one of the earliest biological changes in AD, occurring many years prior to neurodegeneration, and therefore presents a unique opportunity for strategic therapeutic intervention. Here, we have mapped the extent of glymphatic inflow of an MRI contrast agent from cerebrospinal fluid, into the brain parenchyma. Leading on from previous studies, we have demonstrated that glymphatic inflow is impaired during the onset of pathology in an AD animal model.
Introduction
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. Gd-DTPA was infused intracisternally and its whole brain distribution was dynamically imaged in real-time using T1-weighted MRI for a total of 180 minutes. 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 inflow is subtly impaired prior to and during tangle formation in 2.5 month old and 5 month old rTg4510 mice, compared to wildtype animals. At 7.5 months, during the onset of neurodegeneration, glymphatic inflow is elevated in the hippocampus and rostral cortex, and is reduced in the caudal cortex.Discussion & Conclusion
In the rTg4510 model, impaired glymphatic inflow in the caudal cortex is concordant with previous histological findings where aquaporin 4 polarisation (AQP4) was markedly affected in this region during neurodegeneration. 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. We postulate that the cellular changes that occur during disease pathology may contribute to these glymphatics changes, and histological analysis of AQP4 localisation and polarisation in the younger cohorts of rTg4510 during disease onset, will yield whether or not AQP4 polarisation is a prerequisite, or result of tau accumulation in this animal model of tauopathy.1. Iliff J. J, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine 4, 147ra111, doi:10.1126/scitranslmed.3003748 (2012).
2. Harrison, I.F. et al., (2015), Alz&Dementia, Supplement IC-P-160. 11 (7):p.P107.