Abstract
Amyloid-β (Aβ) deposit in the parenchyma is a major characteristic in Alzheimer’s disease (AD), and the impaired glymphatic clearance contributes to the Aβ accumulation. It was reported that L-3-n-butylphthalide (NBP) showed the potential neuroprotective effect in the rodent models of AD. The effects of NBP on the glymphatic system were explored in this study. In the wild-type mice, both CSF tracer influx and perivascular drainage increased after NBP treatment compared with vehicle treatment. Moreover, NBP promoted the perivascular drainage of Aβ via increased cerebral pulsation, which could be inhibited by propranolol. Then, we studied the potential of 3-month NBP treatment on Aβ deposits in 8-month-old APP/PS1 transgenic mice. NBP daily treatments remarkably improved cognitive behavior in Morris water maze. Furthermore, NBP could reduce Aβ deposition and decrease parenchymal Aβ levels. In addition, NBP markedly improved the perivascular AQP4 localization. Our results indicated that NBP could enhance the glymphatic clearance and reduce parenchymal Aβ deposit in the APP/PS1 mice, suggesting that it may have potential in the treatment of AD.
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References
Arbel-Ornath M et al (2013) Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models. Acta Neuropathol 126:353–364
Canter RG, Penney J, Tsai L-H (2016) The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature 539:187–196. https://doi.org/10.1038/nature20412
Da Mesquita S et al (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560:185–191
Iliff JJ et al (2014) Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. The Journal of Neuroscience 34:16180. https://doi.org/10.1523/JNEUROSCI.3020-14.2014
Iliff JJ et al. (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β science translational medicine 4:147ra111 https://doi.org/10.1126/scitranslmed.3003748
Iliff JJ et al. (2013) Cerebral arterial pulsation drives paravascular CSF–interstitial fluid exchange in the murine brain Journal of Neuroscience 33:18190–18199
Kress BT et al (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76:845–861. https://doi.org/10.1002/ana.24271
Liu Q et al (2020) Experimental alcoholism primes structural and functional impairment of the glymphatic pathway Brain. Behavior, and Immunity 85:106–119. https://doi.org/10.1016/j.bbi.2019.06.029
Louveau A et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341
Mawuenyega KG et al (2010) Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 330:1774. https://doi.org/10.1126/science.1197623
Nation DA et al. (2019) Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction Nature Medicine 25:270–276 https://doi.org/10.1038/s41591-018-0297-y
Peng W et al (2016) Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiology of disease 93:215–225
Peng Y et al. (2012) L-3-n-butylphthalide reduces tau phosphorylation and improves cognitive deficits in AβPP/PS1-Alzheimer’s transgenic mice Journal of Alzheimer's Disease 29:379–391 https://doi.org/10.3233/JAD-2011-111577
Peng Y, Sun J, Hon S, Nylander AN, Lemere CA (2010) L-3-n-Butylphthalide improves cognitive impairment and reduces amyloid- in a transgenic model of Alzheimer’s disease Journal of Neuroscience 30:8180–8189
Qin C et al. (2018) Dl-3-N-butylphthalide attenuates ischemic reperfusion injury by improving the function of cerebral artery and circulation Journal of Cerebral Blood Flow & Metabolism 39:2011–2021 https://doi.org/10.1177/0271678X18776833
Rasmussen MK, Mestre H, Nedergaard M (2018) The glymphatic pathway in neurological disorders. The Lancet Neurology 17:1016–1024. https://doi.org/10.1016/S1474-4422(18)30318-1
Ren Z et al. (2013) ‘Hit & Run’ model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation Journal of Cerebral Blood Flow & Metabolism 33:834–845 https://doi.org/10.1038/jcbfm.2013.30
Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM (2016) Alzheimer’s disease The Lancet 388:505–517. https://doi.org/10.1016/S0140-6736(15)01124-1
Shan W et al. (2018) Dl-3-n-butylphthalide (NBP): a promising therapeutic agent for ischemic stroke CNS & neurological disorders - Drug Targets 17:338–347 https://doi.org/10.2174/1871527317666180612125843
Shih AY, Mateo C, Drew PJ, Tsai PS, Kleinfeld D (2012) A polished and reinforced thinned-skull window for long-term imaging of the mouse brain J Vis Exp:3742 https://doi.org/10.3791/3742
Tarasoff-Conway JM et al. (2015) Clearance systems in the brain—implications for Alzheimer disease Nature reviews neurology 11:457
Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease Brain pathology (Zurich, Switzerland) 18:253–266
Yan L et al (2020) Omega-3 polyunsaturated fatty acids promote brain-to-blood clearance of β-amyloid in a mouse model with Alzheimer’s disease Brain. Behavior, and Immunity 85:35–45. https://doi.org/10.1016/j.bbi.2019.05.033
Zeppenfeld DM et al. (2017) Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains JAMA Neurology 74:91–99 doi:https://doi.org/10.1001/jamaneurol.2016.4370
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The study was supported by Guangdong Provincial Science and Technology Plan Project (grant number 2014A020212604) and Guangzhou Science and Technology Plan Project (grant number 2014J4100100).
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Zhang, B., Li, W., Zhuo, Y. et al. L-3-n-Butylphthalide Effectively Improves the Glymphatic Clearance and Reduce Amyloid-β Deposition in Alzheimer’s Transgenic Mice. J Mol Neurosci 71, 1266–1274 (2021). https://doi.org/10.1007/s12031-020-01752-z
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DOI: https://doi.org/10.1007/s12031-020-01752-z