title: An okadaic acid-induced model of tauopathy and cognitive deficiency.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes cognitive and behavioral deterioration in the elderly. Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of AD that has been shown to correlate positively with the severity of dementia in the neocortex of AD patients. In an attempt to characterize an in vivo AD tauopathy model, okadaic acid (OA), a protein phosphatase inhibitor, was microinfused into the right lateral dorsal hippocampus area of ovariectomized adult rat. Cognitive deficiency was seen in OA-treated rats without a change in motor function. Both silver staining and immunohistochemistry staining revealed that OA treatment induces NFTs-like conformational changes in both the cortex and hippocampus. Phosphorylated tau as well as cyclin-dependent kinase 5 (cdk5) and its coactivator, p25, were significantly increased in these regions of the brain. Oxidative stress was also increased with OA treatment as measured by protein carbonylation and lipid peroxidation. These data suggest that the unilateral microinfusion of OA into the dorsal hippocampus causes cognitive deficiency, NFTs-like pathological changes, and oxidative stress as seen in AD pathology via tau hyperphosphorylation caused by inhibition of protein phosphatases.
authors.affiliation: Deptment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D018782:Maze Learning / Q000187:drug effects; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D019319:Okadaic Acid / Q000008:administration & dosage / Q000633:toxicity*; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D019319:Okadaic Acid
references.citation: EMBO J. 1990 Aug;9(8):2431-8
references.pmid: 2164470
references.citation: Trends Neurosci. 2002 Jan;25(1):22-6
references.pmid: 11801334
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3996-4001
references.pmid: 11891272
references.citation: FEBS Lett. 1993 Jul 5;325(3):167-72
references.pmid: 7686508
references.citation: Am J Obstet Gynecol. 1997 Jan;176(1 Pt 1):1-7
references.pmid: 9024081
references.citation: Biochim Biophys Acta. 2007 Apr;1772(4):494-502
references.pmid: 17142016
references.citation: Neuroscience. 1994 Aug;61(4):765-72
references.pmid: 7838376
references.citation: J Biol Chem. 2004 May 21;279(21):22684-92
references.pmid: 14982935
references.citation: Ann N Y Acad Sci. 2005 Jun;1052:210-24
references.pmid: 16024764
references.citation: Eur J Neurosci. 2005 Oct;22(8):1942-50
references.pmid: 16262633
references.citation: Brain Pathol. 1999 Jan;9(1):133-46
references.pmid: 9989456
references.citation: Neurobiol Aging. 1998 Jan-Feb;19(1):3-13
references.pmid: 9562497
references.citation: Neuron. 2003 Apr 10;38(1):127-33
references.pmid: 12691670
references.citation: FEBS Lett. 1994 Mar 14;341(1):94-8
references.pmid: 8137929
references.citation: Science. 2005 Jul 15;309(5733):476-81
references.pmid: 16020737
references.citation: Neuroscience. 1998 Aug;85(4):1337-40
references.pmid: 9681968
references.citation: J Neurochem. 2004 Mar;88(6):1313-26
references.pmid: 15009631
references.citation: Biochemistry. 2004 Aug 17;43(32):10520-31
references.pmid: 15301550
references.citation: Neuropsychopharmacology. 2005 Aug;30(8):1511-20
references.pmid: 15886720
references.citation: J Biol Chem. 1987 Dec 25;262(36):17577-83
references.pmid: 3121601
references.citation: EMBO J. 2001 Jan 15;20(1-2):27-39
references.pmid: 11226152
references.citation: Biochim Biophys Acta. 2005 Jan 3;1739(2-3):331-54
references.pmid: 15615650
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2910-5
references.pmid: 10706614
references.citation: J Cell Sci. 2004 Nov 15;117(Pt 24):5721-9
references.pmid: 15537830
references.citation: Biochim Biophys Acta. 2000 Jul 26;1502(1):139-44
references.pmid: 10899439
references.citation: Pathobiology. 2008;75(3):186-94
references.pmid: 18550916
references.citation: Biochemistry. 2008 Aug 12;47(32):8367-77
references.pmid: 18636751
references.citation: J Biol Chem. 2001 Sep 7;276(36):34298-306
references.pmid: 11441005
references.citation: J Neurochem. 1997 May;68(5):2092-7
references.pmid: 9109537
references.citation: J Neuropathol Exp Neurol. 2006 Jul;65(7):631-41
references.pmid: 16825950
references.citation: Lancet Neurol. 2004 Apr;3(4):219-26
references.pmid: 15039034
references.citation: J Neuropathol Exp Neurol. 2008 Jun;67(6):523-31
references.pmid: 18520771
references.citation: Neurosci Lett. 1992 Nov 23;147(1):58-62
references.pmid: 1336152
references.citation: Nature. 1994 Sep 29;371(6496):419-23
references.pmid: 8090221
references.citation: J Biomed Biotechnol. 2006;2006(3):31825
references.pmid: 17047304
references.citation: Neuroscience. 2003;118(4):1175-82
references.pmid: 12732260
references.citation: J Biol Chem. 1995 Jan 13;270(2):823-9
references.pmid: 7822317
references.citation: Biochem J. 1997 May 1;323 ( Pt 3):577-91
references.pmid: 9169588
references.citation: Cell Mol Life Sci. 2007 Sep;64(17):2219-33
references.pmid: 17604998
references.citation: Prog Neurobiol. 2001 Nov;65(4):391-426
references.pmid: 11527574
references.citation: Nat Med. 2005 Aug;11(8):826-7
references.pmid: 16079873
references.citation: Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7
references.pmid: 3088567
references.citation: Neuron. 2003 Jan 9;37(1):171-80
references.pmid: 12526782
references.citation: Exp Biol Med (Maywood). 2006 May;231(5):514-21
references.pmid: 16636299
references.citation: Nature. 1999 Dec 9;402(6762):615-22
references.pmid: 10604467
references.citation: Neurosci Lett. 1995 Apr 21;189(3):167-9
references.pmid: 7624036
references.citation: Epilepsy Behav. 2007 May;10(3):477-85
references.pmid: 17368105
references.citation: Neuron. 1989 Oct;3(4):519-26
references.pmid: 2484340
references.citation: J Neurochem. 1994 Feb;62(2):803-6
references.pmid: 8294942
references.citation: Brain Res Bull. 1999 Jan 1;48(1):113-9
references.pmid: 10210177
references.citation: Dementia. 1995 Jan-Feb;6(1):21-31
references.pmid: 7728216
references.citation: EMBO J. 1992 Jun;11(6):2131-8
references.pmid: 1376245
references.citation: J Biol Chem. 1992 Aug 5;267(22):15721-8
references.pmid: 1639808
references.citation: Brain Res. 2010 Jul 23;1345:176-81
references.pmid: 20457142
references.citation: Neurology. 1992 Mar;42(3 Pt 1):631-9
references.pmid: 1549228
references.citation: FEBS Lett. 1994 Nov 21;355(1):35-40
references.pmid: 7957957
references.citation: Brain Res. 2004 Oct 1;1022(1-2):30-8
references.pmid: 15353210
references.citation: Neuroscience. 1997 May;78(2):309-24
references.pmid: 9145789
references.citation: Neuropsychologia. 1998 Nov;36(11):1217-38
references.pmid: 9842767
references.citation: J Biol Chem. 1986 May 5;261(13):6084-9
references.pmid: 3084478
references.citation: Proc Natl Acad Sci U S A. 1975 May;72(5):1858-62
references.pmid: 1057175
references.citation: Physiol Rev. 2004 Apr;84(2):361-84
references.pmid: 15044677
references.citation: J Cell Sci. 2007 Aug 15;120(Pt 16):2935-43
references.pmid: 17666435
references.citation: Brain. 2009 May;132(Pt 5):1324-34
references.pmid: 19321462
references.citation: J Neurosci. 1993 Sep;13(9):3916-25
references.pmid: 8366351
references.citation: Ann N Y Acad Sci. 2008 Dec;1147:70-8
references.pmid: 19076432
references.citation: Hippocampus. 1991 Jul;1(3):221-9
references.pmid: 1669368
references.citation: Neuropsychologia. 1997 Jan;35(1):11-24
references.pmid: 8981373
references.citation: Mol Biol Cell. 2007 Dec;18(12):5060-8
references.pmid: 17928404
references.citation: J Biol Chem. 1993 Nov 5;268(31):23512-8
references.pmid: 8226879
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9697-701
references.pmid: 7568200