title: Selective induction of calcineurin activity and signaling by oligomeric amyloid beta.
abstract: Alzheimer's disease (AD) is a terminal age-associated dementia characterized by early synaptic dysfunction and late neurodegeneration. Although the presence of plaques of fibrillar aggregates of the amyloid beta peptide (Abeta) is a signature of AD, evidence suggests that the preplaque small oligomeric Abeta promotes both synaptic dysfunction and neuronal death. We found that young Tg2576 transgenic mice, which accumulate Abeta and develop cognitive impairments prior to plaque deposition, have high central nervous system (CNS) activity of calcineurin (CaN), a phosphatase involved in negative regulation of memory function via inactivation of the transcription factor cAMP responsive element binding proteins (CREB), and display CaN-dependent memory deficits. These results thus suggested the involvement of prefibrillary forms of Abeta. To investigate this issue, we compared the effect of monomeric, oligomeric, and fibrillar Abeta on CaN activity, CaN-dependent pCREB and phosphorylated Bcl-2 Associated death Protein (pBAD) levels, and cell death in SY5Y cells and in rat brain slices, and determined the role of CaN on CREB phosphorylation in the CNS of Tg2576 mice. Our results show that oligomeric Abeta specifically induces CaN activity and promotes CaN-dependent CREB and Bcl-2 Asociated death Protein (BAD) dephosphorylation and cell death. Furthermore, Tg2576 mice display Abeta oligomers and reduced pCREB in the CNS, which is normalized by CaN inhibition. These findings suggest a role for CaN in mediating effects of oligomeric Abeta on neural cells. Because elevated CaN levels have been reported in the CNS of cognitively impaired aged rodents, our results further suggest that abnormal CaN hyperactivity may be a common event exacerbating the cognitive and neurodegenerative impact of oligomeric Abeta in the aging CNS.
authors.affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Texas, USA.
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Reese
authors.forename: WenRu
authors.initials: W
authors.lastname: Zhang
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Dineley
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.forename: Giulio
authors.initials: G
authors.lastname: Taglialatela
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D019703:Calcineurin / Q000096:biosynthesis* / Q000502:physiology; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000737:chemistry / Q000502:physiology; D058255:Protease Nexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D065095:Calcineurin Inhibitors; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D019703:Calcineurin
references.citation: Science. 1999 Apr 9;284(5412):339-43
references.pmid: 10195903
references.citation: Science. 2002 Oct 25;298(5594):789-91
references.pmid: 12399581
references.citation: Biochem Biophys Res Commun. 2001 Jun 8;284(2):310-6
references.pmid: 11394878
references.citation: Neurobiol Aging. 1993 Nov-Dec;14(6):589-96
references.pmid: 8295661
references.citation: Nature. 2006 Mar 16;440(7082):352-7
references.pmid: 16541076
references.citation: Nat Neurosci. 2005 Aug;8(8):1051-8
references.pmid: 16025111
references.citation: Neuroscientist. 2003 Apr;9(2):117-26
references.pmid: 12708616
references.citation: J Neurosci. 2007 Mar 14;27(11):2866-75
references.pmid: 17360908
references.citation: Cell. 1996 Dec 27;87(7):1203-14
references.pmid: 8980227
references.citation: Science. 2003 Apr 18;300(5618):486-9
references.pmid: 12702875
references.citation: J Neurosci. 2001 Jun 1;21(11):4066-73
references.pmid: 11356894
references.citation: Neuron. 2008 Jul 31;59(2):214-25
references.pmid: 18667150
references.citation: Ann Neurol. 1991 Aug;30(2):156-65
references.pmid: 1910274
references.citation: Annu Rev Immunol. 1996;14:483-510
references.pmid: 8717522
references.citation: J Physiol. 2006 Apr 15;572(Pt 2):477-92
references.pmid: 16469784
references.citation: Methods Enzymol. 2006;413:326-44
references.pmid: 17046404
references.citation: Trends Neurosci. 2006 Dec;29(12):679-86
references.pmid: 17084465
references.citation: Aging Cell. 2007 Jun;6(3):319-25
references.pmid: 17517041
references.citation: J Biol Chem. 2005 Jun 10;280(23):22044-52
references.pmid: 15799972
references.citation: Neurosci Lett. 2004 Feb 26;357(1):73-5
references.pmid: 15036616
references.citation: Neurobiol Learn Mem. 2002 May;77(3):354-71
references.pmid: 11991763
references.citation: Nature. 2006 Oct 19;443(7113):774-9
references.pmid: 17051203
references.citation: Neurology. 2006 Jan 24;66(2 Suppl 1):S74-8
references.pmid: 16432151
references.citation: Biochem Biophys Res Commun. 2003 Nov 28;311(4):1195-208
references.pmid: 14623305
references.citation: Eur J Neurosci. 2003 Mar;17(6):1189-96
references.pmid: 12670307
references.citation: Neurobiol Learn Mem. 2004 Sep;82(2):159-63
references.pmid: 15341801
references.citation: Brain Pathol. 2005 Jan;15(1):84-7
references.pmid: 15779241
references.citation: Nature. 2002 Apr 4;416(6880):535-9
references.pmid: 11932745
references.citation: Neurobiol Dis. 2007 Jan;25(1):179-88
references.pmid: 17067805
references.citation: Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
references.pmid: 17245412
references.citation: J Neurosci. 2005 May 4;25(18):4649-58
references.pmid: 15872113
references.citation: Annu Rev Immunol. 1998;16:395-419
references.pmid: 9597135
references.citation: Neurodegeneration. 1995 Mar;4(1):13-21
references.pmid: 7600182
references.citation: Nat Neurosci. 2005 Jan;8(1):79-84
references.pmid: 15608634
references.citation: Brain Res. 2002 Jan 11;924(2):133-40
references.pmid: 11750898
references.citation: Exp Neurol. 2002 Feb;173(2):183-95
references.pmid: 11822882
references.citation: Neurobiol Learn Mem. 2007 Sep;88(2):217-24
references.pmid: 17521929
references.citation: J Neurosci. 2000 Oct 1;20(19):7246-51
references.pmid: 11007881
references.citation: J Biol Chem. 2005 Apr 29;280(17):17294-300
references.pmid: 15722360
references.citation: J Biol Chem. 1999 Mar 5;274(10):6483-92
references.pmid: 10037741
references.citation: Annu Rev Biochem. 2006;75:333-66
references.pmid: 16756495
references.citation: Ann Neurol. 1999 Dec;46(6):860-6
references.pmid: 10589538
references.citation: Biochem Biophys Res Commun. 2003 Nov 28;311(4):1159-71
references.pmid: 14623302
references.citation: Neuromolecular Med. 2004;6(1):53-64
references.pmid: 15781976
references.citation: J Neurosci. 2008 Apr 16;28(16):4231-7
references.pmid: 18417702
references.citation: J Neurosci. 2003 Sep 10;23(23):8310-7
references.pmid: 12967993
references.citation: Cell. 1991 Aug 23;66(4):807-15
references.pmid: 1715244
references.citation: Neuron. 2003 Jul 31;39(3):409-21
references.pmid: 12895417
references.citation: Synapse. 2007 Jan;61(1):24-8
references.pmid: 17068779