4. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN46285, USA ... astrocytes surrounding blood vessels, and quantification of their aquaporin-4 ...
Glymphatic clearance impaired in a mouse model of tauopathy: captured using contrast-enhanced MRI 1
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IF Harrison , A Machhada , N Colgan , O Ismail , JM O'Callaghan , HE Holmes , JA Wells , AV Gourine , T Murray , 3 4 4 3 1 Z Ahmed , RA Johnson , EC Collins , M O'Neill , MF Lythgoe 1. UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, UK 2. Department of Neuroscience, Physiology & Pharmacology, University College London, UK 3. Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, GU206PH, UK 4. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN46285, USA Background and Aims: Alzheimer’s disease (AD) is the most common form of dementia, with prevalence estimated currently to stand at around 24 million, a figure thought to quadruple by the year 2050 due to our ageing population [1]. Neuropathologically, AD is characterised by the formation of two species of toxic protein aggregates in the brain: extracellular accumulation of amyloid-β (Aβ) in the form of plaques, and intracellular accumulation of hyperphosphorylated tau in the form of neurofibrillary tangles (NFTs) [2]. Therefore failure of the clearance mechanisms of Aβ and tau from the brain parenchyma are becoming increasingly recognised in the pathogenesis of AD [3]. A recently described mechanism of solute clearance from the brain is referred to as the ‘glymphatic’ clearance pathway, based on its appropriation of the lymphatic function of interstitial protein management, and its dependence upon glial water transport [4]. In this brain-wide pathway, cerebrospinal fluid (CSF) enters the brain along para-arterial routes via convective bulk flow, where it exchanges with interstitial fluid (ISF) and is cleared from the brain along para-venous routes, taking interstitial solutes with it [4]. Recently this pathway has been imaged using contrast-enhanced MRI and two photon microscopy, demonstrating that Aβ is indeed a substrate for ‘glymphatic’ clearance in mice [5], and that tau follows the same para-venous route of clearance in the mouse brain [6], hence the implication of impairment of this ‘glymphatic’ clearance pathway in AD pathogenesis. Therefore in this study we sought to quantify the extent of ‘glymphatic’ clearance in the brain of an animal model of tauopathy using contrast-enhanced MRI and intracortical injection of tau to determine the effects of pathological tau accumulation on ‘glymphatic’ inflow and tau clearance. Additionally, molecular and cellular analysis of animal brains was utilised to elucidate the mechanism by which glymphatic clearance is achieved and/or is impaired in this model. Methods: Glymphatic inflow in the brains of rTg4510 and litter-matched wildtype mice was captured using contrast-enhanced MRI. Gadolinium was injected intrathecally and its distribution through para-arterial glymphatic exchange channels followed in real time using MRI. Additionally glymphatic clearance of tau from the cortex in these animals was quantified using intracortical injection of tau and its subsequent detection in extracted CSF. Histological examination and laser capture microdissection of astrocytes surrounding blood vessels, and quantification of their aquaporin-4 expression was performed to help understand the involvement of this water channel in mediating changes in glymphatic function in this animal model of tauopathy. Results: Glymphatic inflow of MR contrast agent was significantly impaired in the caudal cortex of rTg4510 mice compared to wildtype animals in line with reduced tau clearance and pathological accumulation of NFTs. Aquaporin-4 expression levels and the extent of astrocytic aquaporin-4 polarisation in this region suggest an involvement of this glial water channel in mediating glymphatic impairment in this animal model of tauopathy. Conclusions: Pathological accumulation of tau in this animal model of tauopathy is associated with impaired glymphatic clearance from the brain. Expression levels of astrocytic aquaporin-4 highlight possible roles of this protein in glymphatic clearance. This is the first investigation of glymphatic clearance in a tau model and warrants further investigation of the mechanisms involved. Furthermore, manipulation of the glymphatic clearance pathway may harbour new avenues of therapeutic intervention for AD. [1] Reitz, C. and R. Mayeux, Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers. Biochemical Pharmacology, 2014. 88(4): p. 640-651. [2] Huang, Y. and L. Mucke, Alzheimer Mechanisms and Therapeutic Strategies. Cell, 2012. 148(6): p. 1204-1222. [3] Tarasoff-Conway, J.M., et al., Clearance systems in the brain[mdash]implications for Alzheimer disease. Nat Rev Neurol, 2015. 11(8): p. 457-470. [4] Jessen, N.A., et al., The Glymphatic System: A Beginner’s Guide. Neurochemical Research, 2015: p. 1-17. [5] Iliff, J.J., et al., A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Science translational medicine, 2012. 4(147): p. 147ra111-147ra111. [6] Iliff, J.J., et al., Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury. The Journal of Neuroscience, 2014. 34(49): p. 16180-16193.
