The brain rinses away Aβ during sleep, powered by glymphatic flow from arteries to veins. In today’s Journal of Experimental Medicine, researchers led by Takeshi Iwatsubo at the University of Tokyo present evidence that this process clears extracellular tau as well, and that it can attenuate neurodegeneration. Tauopathy mice lacking aquaporin 4 (AQP4), which have impaired glymphatic clearance, accumulated more insoluble p-tau in the brain and lost more neurons with age than did those with a working glymphatic system. The clearance may wash away aggregated tau seeds that can spread pathology, Iwatsubo suggested.
- Reducing glymphatic flow slowed the clearance of extracellular tau from mouse brain.
- In tauopathy mice, this caused faster accumulation of insoluble p-tau in neurons.
- Neuron loss accelerated.
“This carefully conducted research identifies AQP4 as an important molecule for extracellular tau transport from brain to CSF via glymphatic system,” noted Tsuneya Ikezu at the Mayo Clinic in Jacksonville, Florida. The data hint that enhancing AQP4 function or increasing its expression might help prevent tau buildup, Ikezu said.
Glymphatic flow was first described by Maiken Nedergaard at the University of Rochester Medical Center, New York, and Jeffrey Iliff, now at the University of Washington in Seattle. They reported that AQP4 water channels on astrocyte endfeet around cerebral blood vessels drive the movement of interstitial fluid along arterioles and veins. This current picks up solutes from the parenchymal extracellular space and washes them into the perivascular space around veins, where they flow from the brain (Aug 2012 news). Later studies found that this drainage, which increases during sleep, helps clear Aβ (Mar 2013 news; Jan 2014 webinar). The efficiency of the system wanes with age, after strokes, and in the Alzheimer’s brain (May 2014 news; Mar 2017 news; Dec 2016 news).
Unlike Aβ, tau is predominantly an intracellular protein, though some is released into the extracellular space, and its level there spikes during wakefulness and sleep deprivation (Jan 2019 news). This led Iwatsubo to wonder whether tau was also cleared by glymph.
To test this, joint first authors Kazuhisa Ishida and Kaoru Yamada injected fluorescently labeled human tau into the striata of wild-type and AQP4 knockout mice. In wild-types, tau diffused through the brain within 12 hours, and was mostly cleared from parenchyma by 48. In the knockouts, by contrast, tau spread more slowly and not as far, and most of it remained in brain tissue at 48 hours.
The brain’s glymphatic system connects to the flow of cerebrospinal fluid. CSF circulates through the brain, entering along arteries and being carried to veins by glymphatic flow before exiting again into the subarachnoid space, carrying solutes with it. These solutes are absorbed by dural lymphatic vessels and transported to deep cervical lymph nodes (Da Mesquita et al., 2018). Thus, the speed with which a molecule flows through the CSF system helps assess the efficiency of glymphatic clearance. In wild-type mice, tau injected into the brain quickly appeared in the CSF, peaking by six hours and nearly gone by 24. In AQP4 knockouts, CSF tau rose slowly, and was still low at 48 hours (see image above). In a separate experiment, the authors injected labeled tau directly into the subarachnoid space, then measured how quickly it arrived in cervical lymph nodes. In wild-type mice, it showed up within an hour after injection, but in knockouts, almost none appeared.
What effect does this slow clearance have on the brain? The authors crossed AQP4 knockouts with PS19 tauopathy mice, which express human tau with the P301S mutation. At six months of age the AQP4-negtive mice had more paired helical filaments of p-tau in the hippocampus and about three times as much total tau in CSF as did PS19 controls. By nine months, the AQP4 knockouts had accumulated about twice as much insoluble p-tau in the hippocampus, midbrain, and cortex as controls. Their cortices were 25 percent thinner, and they had about 20 percent fewer cortical neurons than controls. Altogether, the data suggested that slowing tau clearance triggered neurodegeneration.
Does insoluble tau double because seeds trapped in the interstitial fluid spread to nearby neurons, coaxing their soluble tau to aggregate? The authors will test this idea by injecting labeled tau seeds into wild-type and AQP4 knockout mice, then tracking what happens to them. An alternate possibility is that intracellular and extracellular tau are in equilibrium, so that an excess of the latter leads to buildup of the former, which is then more likely to aggregate, Iwatsubo and Yamada wrote.
“The impact of AQP4 deletion on tau pathology, however, is somewhat modest, and some alternative tau clearance pathway may play a compensatory role,” Ikezu noted. He suggested analyzing the transcriptome of AQP4 knockouts to find gene-expression changes that might help clear tau.
Meanwhile, Iwatsubo plans to examine how plaques, tangles, or neuroinflammation change glymphatic clearance. Intriguingly, a previous study of the rTg4510 tauopathy model found AQP4 was depleted around blood vessels in the brain and tau clearance was slowed, hinting at a possible negative feedback loop between tangle accumulation and impaired clearance (Harrison et al., 2020).
The findings add more weight to the old stricture to get a good night’s rest, since glymphatic flow surges during sleep. Indeed, a recent study linked better sleep quality and duration in older adults with both a stronger glymphatic flow and better scores on tests of language and delayed recall (Siow et al., 2022). Whether there might be therapeutic ways to improve glymphatic clearance is less clear. Iwatsubo noted the existence of at least one AQP4 inhibitor, TGN-020, and one enhancer, TGN-073, that affect glymphatic flow (Huber et al., 2009; Huber et al., 2018). However, these are experimental tools that have not been tested in people.—Madolyn Bowman Rogers
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- Mini Strokes Cause Mega Problems for Brain Cleansing
- Dearth of Water Channels a Sign of ‘Glymphatic’ Breakdown in Alzheimer’s?
- Another Reason to Catch Some Zzzs: Sleep Regulates Tau Release
Research Models Citations
- Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature. 2018 Aug;560(7717):185-191. Epub 2018 Jul 25 PubMed.
- Harrison IF, Ismail O, Machhada A, Colgan N, Ohene Y, Nahavandi P, Ahmed Z, Fisher A, Meftah S, Murray TK, Ottersen OP, Nagelhus EA, O'Neill MJ, Wells JA, Lythgoe MF. Impaired glymphatic function and clearance of tau in an Alzheimer's disease model. Brain. 2020 Aug 1;143(8):2576-2593. PubMed.
- Siow TY, Toh CH, Hsu JL, Liu GH, Lee SH, Chen NH, Fu CJ, Castillo M, Fang JT. Association of Sleep, Neuropsychological Performance, and Gray Matter Volume With Glymphatic Function in Community-Dwelling Older Adults. Neurology. 2022 Feb 22;98(8):e829-e838. Epub 2021 Dec 14 PubMed.
- Huber VJ, Tsujita M, Nakada T. Identification of aquaporin 4 inhibitors using in vitro and in silico methods. Bioorg Med Chem. 2009 Jan 1;17(1):411-7. Epub 2008 Jan 7 PubMed.
- Huber VJ, Igarashi H, Ueki S, Kwee IL, Nakada T. Aquaporin-4 facilitator TGN-073 promotes interstitial fluid circulation within the blood-brain barrier: [17O]H2O JJVCPE MRI study. Neuroreport. 2018 Jun 13;29(9):697-703. PubMed.
- Ishida K, Yamada K, Nishiyama R, Hashimoto T, Nishida I, Abe Y, Yasui M, Iwatsubo T. Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med. 2022 Mar 7;219(3) Epub 2022 Feb 25 PubMed.