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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Cornel Iridoid Glycoside Suppresses Tau Hyperphosphorylation and Aggregation in a Mouse Model of Tauopathy through Increasing Activity of PP2A

Author(s): Denglei Ma, Yi Luo, Rui Huang, Zirun Zhao, Qi Wang, Lin Li* and Lan Zhang*

Volume 16, Issue 14, 2019

Page: [1316 - 1331] Pages: 16

DOI: 10.2174/1567205017666200103113158

Price: $65


Background: rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathy including Alzheimer’s Disease (AD). Cornel Iridoid Glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects of CIG on tau pathology and underlying mechanisms using rTg4510 mice.

Methods: The cognitive functions were detected by Morris water maze and objective recognition tests. Western blotting and immunofluorescence were conducted to measure the levels of phosphorylated tau and related proteins. Serine/threonine phosphatase assay was applied to detect the activity of protein phosphatase 2A (PP2A).

Results: Intragastric administration of CIG for 3 months improved learning and memory abilities, prevented neuronal and synapse loss, halted brain atrophy, elevated levels of synaptic proteins, protected cytoskeleton, reduced tau hyperphosphorylation and aggregation in the brain of rTg4510 mice. In the mechanism studies, CIG increased the activity of PP2A, elevated the methylation of PP2A catalytic C (PP2Ac) at leucine 309, decreased the phosphorylation of PP2Ac at tyrosine 307, and increased protein expression of leucine carboxyl methyltransferase 1 (LCMT-1), protein tyrosine phosphatase 1B (PTP1B), and protein phosphatase 2A phosphatase activator (PTPA) in the brain of rTg4510 mice.

Conclusion: CIG might have the potential to treat tauopathy such as AD via activating PP2A.

Keywords: Cornel iridoid glycoside, rTg4510 mouse, tauopathy, Alzheimer’s disease, tau phosphorylation, protein phosphatase 2A.

Gao Y, Tan L, Yu JT, Tan L. Tau in Alzheimer’s disease: mechanisms and therapeutic strategies. Curr Alzheimer Res 15(3): 283-300. (2018)
[] [PMID: 28413986]
Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I. Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118(1): 53-69. (2009)
[] [PMID: 19184068]
Grill JD, Cummings JL. Current therapeutic targets for the treatment of Alzheimer’s disease. Expert Rev Neurother 10(5): 711-28. (2010)
[] [PMID: 20420492]
Iqbal K, Liu F, Gong CX. Recent developments with tau-based drug discovery. Expert Opin Drug Discov 13(5): 399-410. (2018)
[] [PMID: 29493301]
Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, et al. Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27(14): 3650-62. (2007)
[] [PMID: 17409229]
Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, et al. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 25(46): 10637-47. (2005)
[] [PMID: 16291936]
Sahara N, DeTure M, Ren Y, Ebrahim AS, Kang D, Knight J, et al. Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain. J Alzheimers Dis 33(1): 249-63. (2013)
[] [PMID: 22941973]
Spires TL, Orne JD, SantaCruz K, Pitstick R, Carlson GA, Ashe KH, et al. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol 168(5): 1598-607. (2006)
[] [PMID: 16651626]
Cook C, Dunmore JH, Murray ME, Scheffel K, Shukoor N, Tong J, et al. Severe amygdala dysfunction in a MAPT transgenic mouse model of frontotemporal dementia. Neurobiol Aging 35(7): 1769-77. (2014)
[] [PMID: 24503275]
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309(5733): 476-81. (2005)
[] [PMID: 16020737]
Blackmore T, Meftah S, Murray TK, Craig PJ, Blockeel A, Phillips K, et al. Tracking progressive pathological and functional decline in the rTg4510 mouse model of tauopathy. Alzheimers Res Ther 9(1): 77. (2017)
[] [PMID: 28931441]
Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J Biol Chem 275(8): 5535-44. (2000)
[] [PMID: 10681533]
Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 22(8): 1942-50. (2005)
[] [PMID: 16262633]
Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Terro F. Tau protein phosphatases in Alzheimer’s disease: the leading role of PP2A. Ageing Res Rev 12(1): 39-49. (2013)
[] [PMID: 22771380]
Sontag JM, Sontag E. Protein phosphatase 2A dysfunction in Alzheimer’s disease. Front Mol Neurosci 7(16): 16. (2014)
[PMID: 24653673]
Zhao Q, Wang M. Advance in anti-aging effects of Cornus officinalis and compounds containing Cornus officinalis. Inform Tradit Chin Med 27(1): 113-6. (2010)
Zhao LH, Ding YX, Zhang L, Li L. Cornel iridoid glycoside improves memory ability and promotes neuronal survival in fimbria-fornix transected rats. Eur J Pharmacol 647(1-3): 68-74. (2010)
[] [PMID: 20826142]
Ma D, Wang N, Fan X, Zhang L, Luo Y, Huang R, et al. Protective effects of cornel iridoid glycoside in rats after traumatic brain injury. Neurochem Res 43(4): 959-71. (2018)
[] [PMID: 29492766]
Ma D, Zhu Y, Li Y, Yang C, Zhang L, Li Y, et al. Beneficial effects of cornel iridoid glycoside on behavioral impairment and senescence status in SAMP8 mice at different ages. Behav Brain Res 312(2016): 20-9. (2016)
[ 10.1016/j.bbr.2016.06.008]
Yang CC, Kuai XX, Li YL, Zhang L, Yu JC, Li L, et al. Cornel iridoid glycoside attenuates tau hyperphosphorylation by inhibition of PP2A demethylation. Evid Based Complement Alternat Med 2013 108486 (2013)
[] [PMID: 24454482]
Yang C, Li X, Gao W, Wang Q, Zhang L, Li Y, et al. Cornel iridoid glycoside inhibits tau hyperphosphorylation via regulating cross-talk between GSK-3beta and PP2A signaling. Front Pharmacol 9: 682. (2018)
[] [PMID: 29997510]
Yao RQ, Zhang L, Wang W, Li L. Cornel iridoid glycoside promotes neurogenesis and angiogenesis and improves neurological function after focal cerebral ischemia in rats. Brain Res Bull 79(1): 69-76. (2009)
[] [PMID: 19150488]
DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 9(374): g481. (2017)
[] [PMID: 28123067]
Dai CL, Hu W, Tung YC, Liu F, Gong CX, Iqbal K. Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3 × Tg-AD mice. Alzheimers Res Ther 10(1): 13. (2018)
[] [PMID: 29386065]
Feng Y, Cui Y, Gao JL, Li R, Jiang XH, Tian YX, et al. Neuroprotective effects of resveratrol against traumatic brain injury in rats: Involvement of synaptic proteins and neuronal autophagy. Mol Med Rep 13(6): 5248-54. (2016)
[] [PMID: 27122047]
Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M, et al. Loss of MAP function leads to hippocampal synapse loss and deficits in the Morris Water Maze with aging. J Neurosci 34(21): 7124-36. (2014)
[] [PMID: 24849348]
Murray ME, Lowe VJ, Graff-Radford NR, Liesinger AM, Cannon A, Przybelski SA, et al. Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum. Brain 138(Pt 5): 1370-81. (2015)
[] [PMID: 25805643]
Di J, Cohen LS, Corbo CP, Phillips GR, El Idrissi A, Alonso AD. Abnormal tau induces cognitive impairment through two different mechanisms: synaptic dysfunction and neuronal loss. Sci Rep 6: 20833. (2016)
[] [PMID: 26888634]
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4): 239-59. (1991)
[] [PMID: 1759558]
Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H, et al. Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18(4): 484-96. (2008)
[] [PMID: 18371174]
Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci 33(3): 1024-37. (2013)
[] [PMID: 23325240]
Kopeikina KJ, Polydoro M, Tai HC, Yaeger E, Carlson GA, Pitstick R, et al. Synaptic alterations in the rTg4510 mouse model of tauopathy. J Comp Neurol 521(6): 1334-53. (2013)
[] [PMID: 23047530]
Iqbal K, Liu F, Gong CX, Grundke-Iqbal I. Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7(8): 656-64. (2010)
[] [PMID: 20678074]
Li B, Chohan MO, Grundke-Iqbal I, Iqbal K. Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau. Acta Neuropathol 113(5): 501-11. (2007)
[] [PMID: 17372746]
Sengupta A, Kabat J, Novak M, Wu Q, Grundke-Iqbal I, Iqbal K. Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys 357(2): 299-309. (1998)
[] [PMID: 9735171]
Zhou LX, Zeng ZY, Du JT, Zhao YF, Li YM. The self-assembly ability of the first microtubule-binding repeat from tau and its modulation by phosphorylation. Biochem Biophys Res Commun 348(2): 637-42. (2006)
[] [PMID: 16889747]
Alonso Adel C, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem 279(33): 34873-81. (2004)
[] [PMID: 15190058]
Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K. Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc Natl Acad Sci USA 94(1): 298-303. (1997)
[] [PMID: 8990203]
Laser-Azogui A, Kornreich M, Malka-Gibor E, Beck R. Neurofilament assembly and function during neuronal development. Curr Opin Cell Biol 32: 92-101. (2015)
[] [PMID: 25635910]
Barten DM, Fanara P, Andorfer C, Hoque N, Wong PY, Husted KH, et al. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. J Neurosci 32(21): 7137-45. (2012)
[] [PMID: 22623658]
Brunden KR, Yao Y, Potuzak JS, Ferrer NI, Ballatore C, James MJ, et al. The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer’s disease and related tauopathies. Pharmacol Res 63(4): 341-51. (2011)
[] [PMID: 21163349]
Pritchard SM, Dolan PJ, Vitkus A, Johnson GVW. The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics. J Cell Mol Med 15(8): 1621-35. (2011)
[] [PMID: 21348938]
Iqbal K, Gong CX, Liu F. Hyperphosphorylation-induced tau oligomers. Front Neurol 4: 112. (2013)
[] [PMID: 23966973]
Schroeder S, Joly-Amado A, Soliman A, Sengupta U, Kayed R, Gordon MN, et al. Oligomeric tau-targeted immunotherapy in Tg4510 mice. Alzheimers Res Ther 9(1): 46. (2017)
[] [PMID: 28655349]
Zhou Y, Shi J, Chu D, Hu W, Guan Z, Gong CX, et al. Relevance of phosphorylation and truncation of Tau to the etiopathogenesis of Alzheimer’s disease. Front Aging Neurosci 10: 27. (2018)
[] [PMID: 29472853]
Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25(1): 59-68. (2007)
[] [PMID: 17241267]
Wang JZ, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol 85(2): 148-75. (2008)
[] [PMID: 18448228]
Zeng K, Li M, Hu J, Mahaman YAR, Bao J, Huang F, et al. Ginkgo biloba extract EGb761 attenuates hyperhomocysteinemia-induced AD like Tau hyperphosphorylation and cognitive impairment in rats. Curr Alzheimer Res 15(1): 89-99. (2018)
[PMID: 28847282]
Cheng XS, Zhao KP, Jiang X, Du LL, Li XH, Ma ZW, et al. Nmnat2 attenuates Tau phosphorylation through activation of PP2A. J Alzheimers Dis 36(1): 185-95. (2013)
[] [PMID: 23579329]
Corcoran NM, Martin D, Hutter-Paier B, Windisch M, Nguyen T, Nheu L, et al. Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer’s disease model. J Clin Neurosci 17(8): 1025-33. (2010)
[] [PMID: 20537899]
Xie H, Clarke S. Protein phosphatase 2A is reversibly modified by methyl esterification at its C-terminal leucine residue in bovine brain. J Biol Chem 269(3): 1981-4. (1994)
[PMID: 8294450]
Lee J, Chen Y, Tolstykh T, Stock J. A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proc Natl Acad Sci USA 93(12): 6043-7. (1996)
[] [PMID: 8650216]
Chen J, Martin BL, Brautigan DL. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science 257(5074): 1261-4. (1992)
[] [PMID: 1325671]
Jordens J, Janssens V, Longin S, Stevens I, Martens E, Bultynck G, et al. The protein phosphatase 2A phosphatase activator is a novel peptidyl-prolyl cis/trans-isomerase. J Biol Chem 281(10): 6349-57. (2006)
[] [PMID: 16380387]
Cayla X, Van Hoof C, Bosch M, Waelkens E, Vandekerckhove J, Peeters B, et al. Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A. J Biol Chem 269(22): 15668-75. (1994)
[PMID: 8195217]
Luo DJ, Feng Q, Wang ZH, Sun DS, Wang Q, Wang JZ, et al. Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous tau hyperphosphorylation. J Neurochem 130(6): 816-25. (2014)
[] [PMID: 24821282]
Luo Y, Nie YJ, Shi HR, Ni ZF, Wang Q, Wang JZ, et al. PTPA activates protein phosphatase-2A through reducing its phosphorylation at tyrosine-307 with upregulation of protein tyrosine phosphatase 1B. Biochim Biophys Acta 1833(5): 1235-43. (2013)
[] [PMID: 23428800]
Arnaud L, Chen S, Liu F, Li B, Khatoon S, Grundke-Iqbal I, et al. Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I2(PP2A)/SET. FEBS Lett 585(17): 2653-9. (2011)
[] [PMID: 21806989]
Folch J, Busquets O, Ettcheto M, Sánchez-López E, Castro-Torres RD, Verdaguer E, et al. Memantine for the treatment of dementia: a review on its current and future applications. J Alzheimers Dis 62(3): 1223-40. (2018)
[] [PMID: 29254093]
Li L, Sengupta A, Haque N, Grundke-Iqbal I, Iqbal K. Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration. FEBS Lett 566(1-3): 261-9. (2004)
[] [PMID: 15147906]
Torrez VR, Zimmer ER, Kalinine E, Haas CB, Zenki KC, Muller AP, et al. Memantine mediates astrocytic activity in response to excitotoxicity induced by PP2A inhibition. Neurosci Lett 696(2019): 179-83. (2019)

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