BRAIN and NERVE－神経研究の進歩72巻5号

2020年05月発行

総説

アミロイドβ，タウの脳間質液濃度への影響要因

著者： 栗原正典¹ 坂内太郎² 岩田淳¹

所属機関： ¹東京大学大学院医学系研究科神経内科学 ²東京逓信病院神経内科

ページ範囲：P.525 - P.531

文献概要

アルツハイマー病（AD）において，脳間質はアミロイドβ（Aβ）オリゴマー・凝集体が存在する部位として重要である。またタウ凝集体は神経細胞内に存在するが，タウ凝集は細胞間を伝播することが判明し，脳間質液中のタウも注目されている。本総説では，ADの病態に重要なAβ・タウの脳間質液濃度へ影響を与える要因について，疫学データからADとの関連が知られるものを中心に，これまでの知見をまとめる。

参考文献

1)Lei Y, Han H, Yuan F, Javeed A, Zhao Y: The brain interstitial system: Anatomy, modeling, in vivo measurement, and applications. Prog Neurobiol 157: 230-246, 2017

2)Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, et al: Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol 11: 457-470, 2015

3)Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, et al: A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4: 147ra111, 2012［doi: 10.1126/scitranslmed.3003748］

4)Ringstad G, Vatnehol SAS, Eide PK: Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain 140: 2691-2705, 2017

5)Rasmussen MK, Mestre H, Nedergaard M: The glymphatic pathway in neurological disorders. Lancet Neurol 17: 1016-1024, 2018

6)Albargothy NJ, Johnston DA, MacGregor-Sharp M, Weller RO, Verma A, et al: Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathol 136: 139-152, 2018

7)樋口真人, 田桑弘之: 脳内からの異常タンパク質排出—脳血液関門・グリアリンパシステム. 実験医学37: 866-871, 2019

8)Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, et al: Structural and functional features of central nervous system lymphatic vessels. Nature 523: 337-341, 2015

9)Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, et al: A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212: 991-999, 2015

10)Cirrito JR, May PC, O'Dell MA, Taylor JW, Parsadanian M, et al: In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci 23: 8844-8853, 2003

11)Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, et al: In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci 31: 13110-13117, 2011

12)Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, et al: A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440: 352-357, 2006

13)Kikuchi K, Kidana K, Tatebe T, Tomita T: Dysregulated Metabolism of the Amyloid-β Protein and Therapeutic Approaches in Alzheimer Disease. J Cell Biochem 118: 4183-4190, 2017

14)Cacace R, Sleegers K, Van Broeckhoven C: Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimers Dement 12: 733-748, 2016

15)Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, et al: Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48: 913-922, 2005

16)Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, et al: APP processing and synaptic function. Neuron 37: 925-937, 2003

17)Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T: Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330: 1774, 2010［doi: 10.1126/science.1197623］

18)Marques F, Sousa JC, Sousa N, Palha JA: Blood-brain-barriers in aging and in Alzheimer's disease. Mol Neurodegeneration 8: 38, 2013［doi: 10.1186/1750-1326-8-38］

19)Wang DS, Iwata N, Hama E, Saido TC, Dickson DW: Oxidized neprilysin in aging and Alzheimer's disease brains. Biochem Biophys Res Commun 310: 236-241, 2003

20)Hawkes CA, Härtig W, Kacza J, Schliebs R, Weller RO, et al: Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol 121: 431-443, 2011

21)Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, et al: Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76: 845-861, 2014

22)Silverberg GD, Mayo M, Saul T, Rubenstein E, McGuire D: Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol 2: 506-511, 2003

23)Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, et al: Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature 560: 185-191, 2018

24)Bannai T, Mano T, Chen X, Ohtomo G, Ohtomo R, et al: Chronic cerebral hypoperfusion shifts the equilibrium of amyloid β oligomers to aggregation-prone species with higher molecular weight. Sci Rep 9: 2827, 2019［doi: 10.1038/s41598-019-39494-7］

25)Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, et al: Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med 3: 89ra57, 2011［doi: 10.1126/scitranslmed.3002156］

26)Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G, et al: Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 15: 501-518, 2019

27)Magnoni S, Brody DL: New perspectives on amyloid-beta dynamics after acute brain injury: moving between experimental approaches and studies in the human brain. Arch Neurol 67: 1068-1073, 2010

28)Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, et al: Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science 321: 1221-1224, 2008

29)Schwetye KE, Cirrito JR, Esparza TJ, Mac Donald CL, Holtzman DM, et al: Traumatic brain injury reduces soluble extracellular amyloid-β in mice: a methodologically novel combined microdialysis-controlled cortical impact study. Neurobiol Dis 40: 555-564, 2010

30)Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, et al: Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326: 1005-1007, 2009

31)Xie L, Kang H, Xu Q, Chen MJ, Liao Y, et al: Sleep drives metabolite clearance from the adult brain. Science 342: 373-377, 2013

32)Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, et al: Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol 71: 971-977, 2014

33)Macauley SL, Stanley M, Caesar EE, Yamada SA, Raichle ME, et al: Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J Clin Invest 125: 2463-2467, 2015

34)Wakabayashi T, Yamaguchi K, Matsui K, Sano T, Kubota T, et al: Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease. Mol Neurodegener 14: 15, 2019［doi: 10.1186/s13024-019-0315-7］

35)Hong H, Liu LP, Liao JM, Wang TS, Ye FY, et al: Downregulation of LRP1 at the blood-brain barrier in streptozotocin-induced diabetic mice. Neuropharmacology 56: 1054-1059, 2009

36)Liu LP, Hong H, Liao JM, Wang TS, Wu J, et al: Upregulation of RAGE at the blood-brain barrier in streptozotocin-induced diabetic mice. Synapse 63: 636-642, 2009

37)Vandermeeren M, Mercken M, Vanmechelen E, Six J, van de Voorde A, et al: Detection of tau proteins in normal and Alzheimer's disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 61: 1828-1834, 1993

38)Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, et al: Neuronal activity regulates extracellular tau in vivo. J Exp Med 211: 387-393, 2014

39)Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, et al: Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci 19: 1085-1092, 2016

40)Yamada K: Extracellular Tau and Its Potential Role in the Propagation of Tau Pathology. Front Neurosci 11: 667, 2017［doi: 10.3389/fnins.2017.00667］

41)Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, et al: The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363: 880-884, 2019

42)Zhu Y, Zhan G, Fenik P, Brandes M, Bell P, et al: Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice. J Neurosci 38: 10255-10270, 2018

43)Mohamed NV, Plouffe V, Rémillard-Labrosse G, Planel E, Leclerc N: Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons. Sci Rep 4: 5715, 2014［doi: 10.1038/srep05715］

44)Karch CM, Jeng AT, Goate AM: Extracellular Tau levels are influenced by variability in Tau that is associated with tauopathies. J Biol Chem 287: 42751-42762, 2012

45)Magnoni S, Esparza TJ, Conte V, Carbonara M, Carrabba G, et al: Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury. Brain 135: 1268-1280, 2012

46)Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, et al: Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34: 16180-16193, 2014

47)Patel TK, Habimana-Griffin L, Gao X, Xu B, Achilefu S, et al: Dural lymphatics regulate clearance of extracellular tau from the CNS. Mol Neurodegener 14: 11, 2019［doi: 10.1186/s13024-019-0312-x］

48)Wang J, Jin WS, Bu XL, Zeng F, Huang ZL, et al: Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies. Acta Neuropathol 136: 525-536, 2018