Abstract
The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer's disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer's disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer's disease, and possibly other neurodegenerative diseases alike.
Highlights
Impaired brain clearance mechanisms that result in the accumulation of aberrant proteins that define Alzheimer’s disease, provide new diagnostic and therapeutic opportunity to delay or prevent clinical symptoms
We demonstrate that in a tauopathy model, the cortical accumulation of tau is not solely allied to regional promoter activity, raising the question as to whether the glymphatic system may be involved in regulation of tau clearance in Alzheimer’s disease
We investigated the healthy mouse brain to establish if there was a pattern of glymphatic clearance that could account for the regional nature of cortical tau deposition
Summary
Impaired brain clearance mechanisms that result in the accumulation of aberrant proteins that define Alzheimer’s disease, provide new diagnostic and therapeutic opportunity to delay or prevent clinical symptoms. One such pathway for parenchymal protein clearance, the glymphatic system, has recently been described (Jessen et al, 2015). Alzheimer’s disease is a devastating condition, neuropathologically characterized by the extracellular accumulation of amyloid-b in the form of plaques, and intracellular accumulation of hyperphosphorylated microtubule associated protein tau in the form of neurofibrillary tangles (NFTs). Recent evidence has suggested that the glymphatic system may contribute to a larger portion of parenchymal clearance of these protein species than previously thought (Iliff et al, 2012; Kress et al, 2014; Tarasoff-Conway et al, 2015)
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