title: An experimental rat model of sporadic Alzheimer's disease and rescue of cognitive impairment with a neurotrophic peptide.
abstract: Alzheimer's disease (AD) is multifactorial and, to date, no single cause of the sporadic form of this disease, which accounts for over 99% of the cases, has been established. In AD brain, protein phosphatase-2A (PP2A) activity is known to be compromised due to the cleavage and translocation of its potent endogenous inhibitor, I2PP2A, from the neuronal nucleus to the cytoplasm. Here, we show that adeno-associated virus vector-induced expression of the N-terminal I2NTF and C-terminal I2CTF halves of I2PP2A , also called SET, in brain reproduced key features of AD in Wistar rats. The I2NTF-CTF rats showed a decrease in brain PP2A activity, abnormal hyperphosphorylation and aggregation of tau, a loss of neuronal plasticity and impairment in spatial reference and working memories. To test whether early pharmacologic intervention with a neurotrophic molecule could rescue neurodegeneration and behavioral deficits, 2.5-month-old I2NTF-CTF rats and control littermates were treated for 40 days with Peptide 6, an 11-mer peptide corresponding to an active region of the ciliary neurotrophic factor. Peripheral administration of Peptide 6 rescued neurodegeneration and cognitive deficit in I2NTF-CTF animals by increasing dentate gyrus neurogenesis and mRNA level of brain derived neurotrophic factor. Moreover, Peptide 6-treated I2NTF-CTF rats showed a significant increase in dendritic and synaptic density as reflected by increased expression of synapsin I, synaptophysin and MAP2, especially in the pyramidal neurons of CA1 and CA3 of the hippocampus.
authors.affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolognin
authors.forename: Julie
authors.initials: J
authors.lastname: Blanchard
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Wang
authors.forename: Gustavo
authors.initials: G
authors.lastname: Basurto-Islas
authors.forename: Yunn Chyn
authors.initials: YC
authors.lastname: Tung
authors.forename: Erik
authors.initials: E
authors.lastname: Kohlbrenner
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D055495:Neurogenesis / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism
chemical_list: D020934:Ciliary Neurotrophic Factor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010455:Peptides; C572949:ciliary neurotrophic factor (146-156); D016875:tau Proteins
references.citation: FEBS Lett. 2005 Jan 17;579(2):363-72
references.pmid: 15642345
references.citation: Pathophysiology. 2009 Oct;16(4):273-7
references.pmid: 19278841
references.citation: Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7
references.pmid: 3088567
references.citation: Am J Pathol. 2005 Jun;166(6):1761-71
references.pmid: 15920161
references.citation: Life Sci. 2002 Jan 4;70(7):735-44
references.pmid: 11833737
references.citation: Acta Neuropathol. 2010 Nov;120(5):605-21
references.pmid: 20697724
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6644-9
references.pmid: 21464314
references.citation: Neuron. 2004 Sep 30;44(1):5-21
references.pmid: 15450156
references.citation: J Neurosci. 2005 Feb 2;25(5):1089-94
references.pmid: 15689544
references.citation: Nat Rev Neurosci. 2010 May;11(5):339-50
references.pmid: 20354534
references.citation: J Neuropathol Exp Neurol. 2008 Jan;67(1):78-84
references.pmid: 18091557
references.citation: Ann Neurol. 1991 Oct;30(4):572-80
references.pmid: 1789684
references.citation: Cell. 2001 Jan 12;104(1):119-30
references.pmid: 11163245
references.citation: Anat Rec. 1991 Dec;231(4):482-97
references.pmid: 1793176
references.citation: Mol Neurodegener. 2007 Jun 09;2:11
references.pmid: 17559680
references.citation: FASEB J. 2005 Nov;19(13):1905-7
references.pmid: 16162853
references.citation: Eur J Neurosci. 2007 Jan;25(1):59-68
references.pmid: 17241267
references.citation: FASEB J. 2010 Nov;24(11):4420-32
references.pmid: 20651003
references.citation: J Neurosci. 2010 Jun 2;30(22):7516-27
references.pmid: 20519526
references.citation: J Neural Transm (Vienna). 2003 Nov;110(11):1313-27
references.pmid: 14628195
references.citation: Science. 2002 Oct 25;298(5594):789-91
references.pmid: 12399581
references.citation: J Neurochem. 1993 Jun;60(6):2068-77
references.pmid: 7684067
references.citation: Neurology. 1999 Dec 10;53(9):1942-7
references.pmid: 10599762
references.citation: J Neurosci. 2008 Feb 27;28(9):2231-41
references.pmid: 18305256
references.citation: Regen Med. 2006 Jan;1(1):15-28
references.pmid: 17465817
references.citation: Genes Dev. 2004 Aug 1;18(15):1806-11
references.pmid: 15289455
references.citation: J Biol Chem. 2002 Mar 1;277(9):7324-32
references.pmid: 11741927
references.citation: Mol Interv. 2007 Oct;7(5):261-70
references.pmid: 17932415
references.citation: Biochemistry. 1995 Feb 14;34(6):1988-96
references.pmid: 7531497
references.citation: Nature. 1982 Jun 24;297(5868):681-3
references.pmid: 7088155
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: Anal Biochem. 1976 Jan;70(1):241-50
references.pmid: 1259145
references.citation: J Neuropathol Exp Neurol. 1997 Aug;56(8):933-44
references.pmid: 9258263
references.citation: Neuron. 1999 Oct;24(2):401-14
references.pmid: 10571233
references.citation: Science. 2008 Mar 21;319(5870):1683-7
references.pmid: 18309046
references.citation: Brain Res. 1988 Aug;464(1):43-52
references.pmid: 3141008
references.citation: J Biol Chem. 1993 Nov 15;268(32):24374-84
references.pmid: 8226987
references.citation: JAMA. 2000 Mar 22-29;283(12):1571-7
references.pmid: 10735393
references.citation: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7571-6
references.pmid: 19372372
references.citation: J Biol Chem. 2000 Feb 25;275(8):5535-44
references.pmid: 10681533
references.citation: Neuron. 2011 Jan 27;69(2):203-13
references.pmid: 21262461
references.citation: Annu Rev Biochem. 2003;72:609-42
references.pmid: 12676795
references.citation: Biochem Biophys Res Commun. 1984 May 16;120(3):885-90
references.pmid: 6375662
references.citation: Acta Neuropathol. 2003 Mar;105(3):225-32
references.pmid: 12557008
references.citation: J Neural Transm (Vienna). 2000;107(4):451-61
references.pmid: 11215756
references.citation: Neuron. 2007 May 24;54(4):559-66
references.pmid: 17521569
references.citation: Neuron. 2002 Nov 14;36(4):675-88
references.pmid: 12441056
references.citation: Proc Natl Acad Sci U S A. 1990 Aug;87(15):5827-31
references.pmid: 2116006
references.citation: J Neurosci. 2000 Sep 15;20(18):6888-97
references.pmid: 10995833
references.citation: J Neurochem. 1993 Sep;61(3):921-7
references.pmid: 8395566
references.citation: FEBS Lett. 2006 Jun 26;580(15):3582-8
references.pmid: 16753151
references.citation: Future Med Chem. 2011 May;3(7):821-33
references.pmid: 21644827
references.citation: Acta Neuropathol. 2011 Nov;122(5):543-9
references.pmid: 21959585
references.citation: Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8856-60
references.pmid: 7568031
references.citation: World J Biol Chem. 2010 May 26;1(5):81-4
references.pmid: 21540993
references.citation: FEBS Lett. 1998 Apr 17;426(2):248-54
references.pmid: 9599018
references.citation: J Cell Mol Med. 2008 Jan-Feb;12(1):38-55
references.pmid: 18194444
references.citation: Methods. 2002 Oct;28(2):158-67
references.pmid: 12413414
references.citation: Learn Mem. 2003 Mar-Apr;10(2):86-98
references.pmid: 12663747
references.citation: Learn Mem. 2002 Sep-Oct;9(5):224-37
references.pmid: 12359832
references.citation: J Biol Chem. 2006 Dec 22;281(51):39413-23
references.pmid: 17056594
references.citation: J Neuropathol Exp Neurol. 2004 Apr;63(4):287-301
references.pmid: 15099019
references.citation: J Neurosci. 2009 Aug 12;29(32):10131-43
references.pmid: 19675247
references.citation: J Alzheimers Dis. 2010;21(4):1185-95
references.pmid: 20952820
references.citation: Cell. 2008 Feb 22;132(4):645-60
references.pmid: 18295581
references.citation: Nat Neurosci. 2007 Mar;10(3):355-62
references.pmid: 17277773
references.citation: Exp Neurol. 2001 Apr;168(2):402-12
references.pmid: 11259128
references.citation: Neurobiol Aging. 2011 Aug;32(8):1420-34
references.pmid: 19767127
references.citation: Neuron. 2007 Feb 1;53(3):337-51
references.pmid: 17270732
references.citation: Neuron. 1991 Nov;7(5):695-702
references.pmid: 1742020
references.citation: Acta Neuropathol. 2009 Jul;118(1):167-79
references.pmid: 19390859
references.citation: Eur J Neurosci. 2005 Oct;22(8):1942-50
references.pmid: 16262633
references.citation: Neuron. 2003 Jul 31;39(3):409-21
references.pmid: 12895417
references.citation: Arch Neurol. 2000 Jun;57(6):846-51
references.pmid: 10867782
references.citation: J Neurosci. 2011 May 25;31(21):7691-9
references.pmid: 21613482