Mitotic mechanisms in Alzheimer's disease?

doi:10.1083/jcb.132.3.413

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Mitotic mechanisms in Alzheimer's disease?

I Vincent, M Rosado and P Davies
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

The mechanism(s) leading to widespread hyper-phosphorylation of proteins in Alzheimer's disease (AD) are unknown. We have characterized seven new monoclonal antibodies recognizing independent phospho- epitopes in the paired helical filament proteins (PHF) found in AD brain. These antibodies show pronounced immunoreactivity with cultured human neuroblastoma cells that are in the M phase of cell division, but have no discernible reactivity with interphase cells. Immunoreactivity with these antibodies does not localize to the microtubule spindles or chromosomes in M phase, but is confined to the surrounding cytoplasm. Similar staining in M phase is observed with cultured cells of various tissue types and species. Cells arrested in M phase with the microtubule depolymerizing agent, nocodazole, show marked increases in immunoreactivity with the antibodies by immunofluorescence staining, ELISA, and immunoblotting. In neuroblastoma cells, the appearance of the TG/MC phospho-epitopes coincides with activation of mitotic protein kinases, but not with the activity of the neuronal specific cyclin- dependent kinase, cdk5. These data suggest that the TG/MC epitopes are conserved mitotic phospho-epitopes produced as a result of increased mitotic kinase activity. To investigate this possibility in AD, we examined the staining of human brain tissue with MPM-2, a marker antibody for mitotic phospho-epitopes. It was found that MPM-2 reacts strongly with neurofibrillary tangles, neuritic processes, and neurons in AD but has no staining in normal human brain. Our data suggest that accumulation of phospho-epitopes in AD may result from activation of mitotic posttranslational mechanisms which do not normally operate in mature neurons of brain.
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Copani, A., Melchiorri, D., Caricasole, A., Martini, F., Sale, P., Carnevale, R., Gradini, R., Sortino, M. A., Lenti, L., De Maria, R., Nicoletti, F. (2002). beta -Amyloid-Induced Synthesis of the Ganglioside Gd3 Is a Requisite for Cell Cycle Reactivation and Apoptosis in Neurons. J. Neurosci. 22: 3963-3968 [Abstract] [Full Text]
Honer, W. G., Falkai, P., Bayer, T. A., Xie, J., Hu, L., Li, H.-Y., Arango, V., Mann, J. J., Dwork, A. J., Trimble, W. S. (2002). Abnormalities of SNARE Mechanism Proteins in Anterior Frontal Cortex in Severe Mental Illness. Cereb Cortex 12: 349-356 [Abstract] [Full Text]
Jordan-Sciutto, K. L., Wang, G., Murphey-Corb, M., Wiley, C. A. (2002). Cell Cycle Proteins Exhibit Altered Expression Patterns in Lentiviral-Associated Encephalitis. J. Neurosci. 22: 2185-2195 [Abstract] [Full Text]
Zamora-Leon, S. P., Lee, G., Davies, P., Shafit-Zagardo, B. (2001). Binding of Fyn to MAP-2c through an SH3 Binding Domain. REGULATION OF THE INTERACTION BY ERK2. J. Biol. Chem. 276: 39950-39958 [Abstract] [Full Text]
Yang, Y., Geldmacher, D. S., Herrup, K. (2001). DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease. J. Neurosci. 21: 2661-2668 [Abstract] [Full Text]
Ding, X.-L., Husseman, J., Tomashevski, A., Nochlin, D., Jin, L.-W., Vincent, I. (2000). The Cell Cycle Cdc25A Tyrosine Phosphatase Is Activated in Degenerating Postmitotic Neurons in Alzheimer's Disease. Am. J. Pathol. 157: 1983-1990 [Abstract] [Full Text]
Roberge, M., Cinel, B., Anderson, H. J., Lim, L., Jiang, X., Xu, L., Bigg, C. M., Kelly, M. T., Andersen, R. J. (2000). Cell-based Screen for Antimitotic Agents and Identification of Analogues of Rhizoxin, Eleutherobin, and Paclitaxel in Natural Extracts. Cancer Res. 60: 5052-5058 [Abstract] [Full Text]
Chen, Y., McPhie, D. L., Hirschberg, J., Neve, R. L. (2000). The Amyloid Precursor Protein-binding Protein APP-BP1 Drives the Cell Cycle through the S-M Checkpoint and Causes Apoptosis in Neurons. J. Biol. Chem. 275: 8929-8935 [Abstract] [Full Text]
COPANI, A., CONDORELLI, F., CARUSO, A., VANCHERI, C., SALA, A., GIUFFRIDA STELLA, A. M., CANONICO, P. L., NICOLETTI, F., SORTINO, M. A. (1999). Mitotic signaling by {beta}-amyloid causes neuronal death. FASEB J. 13: 2225-2234 [Abstract] [Full Text]
Ghoshal, N., Smiley, J. F., DeMaggio, A. J., Hoekstra, M. F., Cochran, E. J., Binder, L. I., Kuret, J. (1999). A New Molecular Link between the Fibrillar and Granulovacuolar Lesions of Alzheimer's Disease. Am. J. Pathol. 155: 1163-1172 [Abstract] [Full Text]
Gieffers, C., Peters, B. H., Kramer, E. R., Dotti, C. G., Peters, J.-M. (1999). Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons. Proc. Natl. Acad. Sci. USA 96: 11317-11322 [Abstract] [Full Text]
LeBlanc, A., Liu, H., Goodyer, C., Bergeron, C., Hammond, J. (1999). Caspase-6 Role in Apoptosis of Human Neurons, Amyloidogenesis, and Alzheimer's Disease. J. Biol. Chem. 274: 23426-23436 [Abstract] [Full Text]
Janicki, S. M., Monteiro, M. J. (1999). Presenilin Overexpression Arrests Cells in the G1 Phase of the Cell Cycle : Arrest Potentiated by the Alzheimer's Disease PS2(N141I)Mutant. Am. J. Pathol. 155: 135-144 [Abstract] [Full Text]
Stumptner, C., Heid, H., Fuchsbichler, A., Hauser, H., Mischinger, H.-J., Zatloukal, K., Denk, H. (1999). Analysis of Intracytoplasmic Hyaline Bodies in a Hepatocellular Carcinoma : Demonstration of p62 as Major Constituent. Am. J. Pathol. 154: 1701-1710 [Abstract] [Full Text]
Illenberger, S., Zheng-Fischhöfer, Q., Preuss, U., Stamer, K., Baumann, K., Trinczek, B., Biernat, J., Godemann, R., Mandelkow, E.-M., Mandelkow, E. (1998). The Endogenous and Cell Cycle-dependent Phosphorylation of tau Protein in Living Cells: Implications for Alzheimer's Disease. Mol. Biol. Cell 9: 1495-1512 [Abstract] [Full Text]
Busser, J., Geldmacher, D. S., Herrup, K. (1998). Ectopic Cell Cycle Proteins Predict the Sites of Neuronal Cell Death in Alzheimer's Disease Brain. J. Neurosci. 18: 2801-2807 [Abstract] [Full Text]
Lee, G, Newman, S., Gard, D., Band, H, Panchamoorthy, G (1998). Tau interacts with src-family non-receptor tyrosine kinases. J. Cell Sci. 111: 3167-3177 [Abstract]
Vincent, I., Jicha, G., Rosado, M., Dickson, D. W. (1997). Aberrant Expression of Mitotic Cdc2/Cyclin B1 Kinase in Degenerating Neurons of Alzheimer's Disease Brain. J. Neurosci. 17: 3588-3598 [Abstract] [Full Text]
Carmel, G., Mager, E. M., Binder, L. I., Kuret, J. (1996). The Structural Basis of Monoclonal Antibody Alz50's Selectivity for Alzheimer's Disease Pathology. J. Biol. Chem. 271: 32789-32795 [Abstract] [Full Text]