title: Retinoblastoma protein phosphorylation at multiple sites is associated with neurofibrillary pathology in Alzheimer disease.
abstract: The re-expression of multiple cell cycle markers representing various cell cycle phases in postmitotic pyramidal neurons suggests that neurons in Alzheimer disease (AD) attempt to re-enter the cell cycle. Entry into the cell cycle requires activation of G1 to S phase cell cycle proteins, among which retinoblastoma protein (pRb) is a key regulator. pRb inhibits the transcription of cell cycle proteins in the nucleus of healthy cells by interaction and consequent blocking of the active site of E2F, dependent upon the phosphate stoichiometry and combination of the locations of their 16 potential phosphorylation sites on pRb. Therefore, to determine whether pRb is involved in the aberrant cell cycle phenotype in AD neurons, a systematic immunocytochemical evaluation of the phosphorylation status of pRb protein using antibodies specific for multiple phosphorylation sites (i.e., pSpT249/252, pS612, pS795, pS807, pS811 and pT821) was carried out in the hippocampal regions of brains from AD patients. Increased levels of phospho-pRb (ppRb) for all these phosphorylation sites were noted in the brains of AD patients as compared to control cases. More importantly, redistribution of ppRb from the nucleus to the cytoplasm of susceptible neurons, with significant localization in neurofibrillary tangles and neuritic plaques, was observed. Additional studies revealed extensive co-localization between phospho-p38 and ppRb, implicating that p38 activation may contribute to cell cycle abnormalities through pRb phosphorylation. Taken together, these data supports the concept of neuronal cell cycle re-entry in AD and indicates a crucial role for pRb in this process.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Thakur
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.forename: Sheronica L
authors.initials: SL
authors.lastname: James
authors.forename: David J
authors.initials: DJ
authors.lastname: Bonda
authors.forename: Akanksha
authors.initials: A
authors.lastname: Rao
authors.forename: Kate M
authors.initials: KM
authors.lastname: Webber
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
authors.forename: Mercé
authors.initials: M
authors.lastname: Pallàs
authors.forename: Gemma
authors.initials: G
authors.lastname: Casadesus
authors.forename: Hyoung-Gon
authors.initials: HG
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Bowser
authors.forename: Arun K
authors.initials: AK
authors.lastname: Raina
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
references.citation: Mol Cell Biol. 1993 Jun;13(6):3384-91
references.pmid: 8497257
references.citation: Med Hypotheses. 1999 Jun;52(6):525-7
references.pmid: 10459833
references.citation: Mech Ageing Dev. 2001 Dec;123(1):11-20
references.pmid: 11640947
references.citation: Biochim Biophys Acta. 2007 Apr;1772(4):494-502
references.pmid: 17142016
references.citation: Genes Dev. 1993 Jul;7(7A):1111-25
references.pmid: 8319904
references.citation: EMBO J. 1994 Jan 1;13(1):118-27
references.pmid: 8306955
references.citation: J Biol Chem. 2005 Oct 28;280(43):35992-8
references.pmid: 16126730
references.citation: Neurobiol Aging. 2000 Nov-Dec;21(6):807-13
references.pmid: 11124424
references.citation: Stem Cells. 2001;19(1):88-91
references.pmid: 11209094
references.citation: Neuroreport. 1996 Nov 25;7(18):3047-9
references.pmid: 9116237
references.citation: J Neuropathol Exp Neurol. 2002 Apr;61(4):358-67
references.pmid: 11939591
references.citation: Neurobiol Aging. 2000 Nov-Dec;21(6):837-41
references.pmid: 11124427
references.citation: Acta Neuropathol. 2002 Oct;104(4):369-76
references.pmid: 12200623
references.citation: Arch Neurol. 1985 Nov;42(11):1097-105
references.pmid: 2864910
references.citation: Mol Cell Biol. 1998 Feb;18(2):753-61
references.pmid: 9447971
references.citation: Aging Cell. 2003 Apr;2(2):105-10
references.pmid: 12882323
references.citation: Acta Neurobiol Exp (Wars). 2004;64(1):81-7
references.pmid: 15190682
references.citation: J Neuropathol Exp Neurol. 2000 Oct;59(10):880-8
references.pmid: 11079778
references.citation: Int J Med Sci. 2007 May 12;4(3):140-5
references.pmid: 17505559
references.citation: Am J Pathol. 2000 Aug;157(2):497-507
references.pmid: 10934153
references.citation: Nat Cell Biol. 2000 Apr;2(4):E65-7
references.pmid: 10783254
references.citation: Neurology. 1991 Apr;41(4):479-86
references.pmid: 2011243
references.citation: Acta Neuropathol. 1997 Mar;93(3):294-300
references.pmid: 9083562
references.citation: Int J Exp Pathol. 1999 Apr;80(2):71-6
references.pmid: 10469261
references.citation: Curr Opin Genet Dev. 1998 Feb;8(1):21-7
references.pmid: 9529601
references.citation: Mech Ageing Dev. 2001 Dec;123(1):39-46
references.pmid: 11640950
references.citation: J Neurochem. 2003 Jul;86(1):136-42
references.pmid: 12807433
references.citation: Mol Cell Biol. 2001 Jul;21(14):4773-84
references.pmid: 11416152
references.citation: Acta Neuropathol. 1997 Jul;94(1):6-15
references.pmid: 9224524
references.citation: Cell. 1991 Jun 14;65(6):1053-61
references.pmid: 1828392
references.citation: Eur J Biochem. 1997 Jun 15;246(3):581-601
references.pmid: 9219514
references.citation: Int Rev Neurobiol. 1998;42:1-54
references.pmid: 9476170
references.citation: J Alzheimers Dis. 2001 Aug;3(4):377-385
references.pmid: 12214040
references.citation: J Alzheimers Dis. 2002 Jun;4(3):249-54
references.pmid: 12226545
references.citation: Neurochem Res. 2007 Apr-May;32(4-5):639-44
references.pmid: 17006760
references.citation: Oncogene. 2005 Apr 18;24(17):2796-809
references.pmid: 15838516
references.citation: J Neurosci Res. 2004 Mar 1;75(5):698-703
references.pmid: 14991845
references.citation: J Neurosci. 2003 Apr 1;23(7):2557-63
references.pmid: 12684440
references.citation: Neuroreport. 1999 Aug 2;10(11):2411-5
references.pmid: 10439473
references.citation: J Cell Biol. 1996 Feb;132(3):413-25
references.pmid: 8636218
references.citation: J Neurochem. 2001 Oct;79(2):311-8
references.pmid: 11677259
references.citation: J Alzheimers Dis. 2004 Apr;6(2):165-9
references.pmid: 15096700
references.citation: Acta Neuropathol. 2003 May;105(5):524-8
references.pmid: 12677454
references.citation: Neurosci Res. 1999 May;34(1):21-9
references.pmid: 10413323
references.citation: J Biol Chem. 2003 May 23;278(21):19358-66
references.pmid: 12646568
references.citation: J Biol Chem. 1997 Nov 7;272(45):28328-34
references.pmid: 9353289
references.citation: Cell. 1991 May 3;65(3):381-93
references.pmid: 2018973
references.citation: Mol Cell Biol. 1997 Oct;17(10):5771-83
references.pmid: 9315635
references.citation: Neuroscience. 1998 Dec;87(4):731-9
references.pmid: 9759963
references.citation: Am J Pathol. 1997 Jun;150(6):1933-9
references.pmid: 9176387
references.citation: J Neurosci. 1997 May 15;17(10):3588-98
references.pmid: 9133382
references.citation: Mol Cell Biol. 1999 May;19(5):3246-56
references.pmid: 10207050
references.citation: Neurobiol Dis. 2004 Apr;15(3):492-9
references.pmid: 15056456