IJCEP Copyright © 2007-All rights reserved.
Int J Clin Exp Pathol 1(2):134-146;2008

Original Article
Retinoblastoma Protein Phosphorylation at Multiple Sites is Associated with
Neurofibrillary Pathology in Alzheimer Disease

Akanksha Thakur, Sandra L. Siedlak, Sheronica L. James, David J. Bonda, Akanksha Rao, Kate M. Webber, Antoni Camins, Mercé Pallàs,
Gemma Casadesus, Hyoung-gon Lee, Robert Bowser, Arun K. Raina, George Perry, Mark A. Smith and Xiongwei Zhu

Department of Pathology and 3Neurosciences, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio, USA; Unitat de
Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain;
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; College of Science, University of Texas at
San Antonio, San Antonio, Texas, USA

Received 19 July 2007; accepted 22 July 2007; available online 1 January 2008

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.

Key Words: Alzheimer disease, cell cycle, hyperphosphorylation, p38, retinoblastoma protein

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Address all correspondence to:  Xiongwei Zhu, PhD, Department of Pathology, Case Western Reserve University, 2103 Cornell Road,
Cleveland, Ohio 44106 USA, Tel: 216-368-5903, Fax: 216-368-8964, Email: