This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rohn, T. T. Articles by Cribbs, D. H. Search for Related Content PubMed PubMed Citation Articles by Rohn, T. T. Articles by Cribbs, D. H.

(American Journal of Pathology. 2001;158:189-198.)
© 2001 American Society for Investigative Pathology

Regular Articles

Correlation between Caspase Activation and Neurofibrillary Tangle Formation in Alzheimer’s Disease

Troy T. Rohn^*, Elizabeth Head^*, Joseph H. Su^*, Aileen J. Anderson^*, Ben A. Bahr, Carl W. Cotman^* and David H. Cribbs^*

From the Institute for Brain Aging and Dementia,^*
University of California at Irvine, Irvine, California; and the Department of Pharmaceutical Sciences and the Neurosciences Program,
University of Connecticut, Storrs, Connecticut

Although evidence suggests that neurofibrillary tangles (NFTs) and neuronal cell loss are prominent features of Alzheimer’s disease (AD), the relationship between the two remains unknown. In the present study, the relationship between the activation of apoptotic mechanisms and NFT formation in AD was investigated using a caspase-cleavage site-directed antibody to fodrin, an abundant neuronal cytoskeleton protein. This antibody recognized cleavage products of fodrin after digestion by caspase-3, but did not recognize full-length fodrin. In vitro analysis of this fodrin caspase-cleavage product (CCP) antibody demonstrates that it is a specific probe for the detection of apoptotic but not necrotic pathways in cultured neurons. To determine whether caspases cleave fodrin in vivo, tissue sections from controls and AD were immunostained for fodrin (CCPs). Although no staining was observed in control cases, labeling of neurons was observed in the hippocampus of all AD cases, which increased as a function of disease progression. To determine a possible relationship between caspase activation and NFT formation, double-labeling experiments with fodrin CCP and PHF-1 were performed. Co-localization of these markers was observed in many neurons, and quantitative analysis showed that as the extent of NFT formation increased, there was a significant corresponding increase in fodrin CCP immunolabeling (r = 0.84). Taken together, these results provide evidence for the activation of apoptotic mechanisms in neurons in the AD brain and suggest that there is an association between NFT formation and the activation of apoptotic pathways in AD.

This article has been cited by other articles:

				D.-S. Yang, A. Kumar, P. Stavrides, J. Peterson, C. M. Peterhoff, M. Pawlik, E. Levy, A. M. Cataldo, and R. A. Nixon Neuronal Apoptosis and Autophagy Cross Talk in Aging PS/APP Mice, a Model of Alzheimer's Disease Am. J. Pathol., September 1, 2008; 173(3): 665 - 681. [Abstract] [Full Text] [PDF]

				T. L. Spires-Jones, A. de Calignon, T. Matsui, C. Zehr, R. Pitstick, H.-Y. Wu, J. D. Osetek, P. B. Jones, B. J. Bacskai, M. B. Feany, et al. In Vivo Imaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons J. Neurosci., January 23, 2008; 28(4): 862 - 867. [Abstract] [Full Text] [PDF]

				D. Goldblum, A. Kipfer-Kauer, G.-M. Sarra, S. Wolf, and B. E. Frueh Distribution of Amyloid Precursor Protein and Amyloid-{beta} Immunoreactivity in DBA/2J Glaucomatous Mouse Retinas Invest. Ophthalmol. Vis. Sci., November 1, 2007; 48(11): 5085 - 5090. [Abstract] [Full Text] [PDF]

				B. F. Jones, J. Barnes, H. B.M. Uylings, N. C. Fox, C. Frost, M. P. Witter, and P. Scheltens Differential Regional Atrophy of the Cingulate Gyrus in Alzheimer Disease: A Volumetric MRI Study Cereb Cortex, December 1, 2006; 16(12): 1701 - 1708. [Abstract] [Full Text] [PDF]

				P. E. Mouser, E. Head, K.-H. Ha, and T. T. Rohn Caspase-Mediated Cleavage of Glial Fibrillary Acidic Protein within Degenerating Astrocytes of the Alzheimer's Disease Brain Am. J. Pathol., March 1, 2006; 168(3): 936 - 946. [Abstract] [Full Text] [PDF]

				A. Fifre, I. Sponne, V. Koziel, B. Kriem, F. T. Y. Potin, B. E. Bihain, J.-L. Olivier, T. Oster, and T. Pillot Microtubule-associated Protein MAP1A, MAP1B, and MAP2 Proteolysis during Soluble Amyloid {beta}-Peptide-induced Neuronal Apoptosis: SYNERGISTIC INVOLVEMENT OF CALPAIN AND CASPASE-3 J. Biol. Chem., January 6, 2006; 281(1): 229 - 240. [Abstract] [Full Text] [PDF]

				S.-Y. Park and A. Ferreira The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates {beta}-Amyloid-Induced Neurodegeneration J. Neurosci., June 1, 2005; 25(22): 5365 - 5375. [Abstract] [Full Text] [PDF]

				J.-H. Cho and G. V. W. Johnson Glycogen Synthase Kinase 3{beta} Induces Caspase-cleaved Tau Aggregation in Situ J. Biol. Chem., December 24, 2004; 279(52): 54716 - 54723. [Abstract] [Full Text] [PDF]

				P. M. Horowitz, K. R. Patterson, A. L. Guillozet-Bongaarts, M. R. Reynolds, C. A. Carroll, S. T. Weintraub, D. A. Bennett, V. L. Cryns, R. W. Berry, and L. I. Binder Early N-Terminal Changes and Caspase-6 Cleavage of Tau in Alzheimer's Disease J. Neurosci., September 8, 2004; 24(36): 7895 - 7902. [Abstract] [Full Text] [PDF]

				D. H. Cribbs, W. W. Poon, R. A. Rissman, and M. Blurton-Jones Caspase-Mediated Degeneration in Alzheimer's Disease Am. J. Pathol., August 1, 2004; 165(2): 353 - 355. [Full Text] [PDF]

				H. Guo, S. Albrecht, M. Bourdeau, T. Petzke, C. Bergeron, and A. C. LeBlanc Active Caspase-6 and Caspase-6-Cleaved Tau in Neuropil Threads, Neuritic Plaques, and Neurofibrillary Tangles of Alzheimer's Disease Am. J. Pathol., August 1, 2004; 165(2): 523 - 531. [Abstract] [Full Text] [PDF]

				P. N. Pompl, S. Yemul, Z. Xiang, L. Ho, V. Haroutunian, D. Purohit, R. Mohs, and G. M. Pasinetti Caspase Gene Expression in the Brain as a Function of the Clinical Progression of Alzheimer Disease Arch Neurol, March 1, 2003; 60(3): 369 - 376. [Abstract] [Full Text] [PDF]

				Y.-H. Suh and F. Checler Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease Pharmacol. Rev., September 1, 2002; 54(3): 469 - 525. [Abstract] [Full Text] [PDF]

				S. Kahns, S. Lykkebo, L. D. Jakobsen, M. S. Nielsen, and P. H. Jensen Caspase-mediated Parkin Cleavage in Apoptotic Cell Death J. Biol. Chem., May 3, 2002; 277(18): 15303 - 15308. [Abstract] [Full Text] [PDF]

				S. J. McKinnon, D. M. Lehman, L. A. Kerrigan-Baumrind, C. A. Merges, M. E. Pease, D. F. Kerrigan, N. L. Ransom, N. G. Tahzib, H. A. Reitsamer, H. Levkovitch-Verbin, et al. Caspase Activation and Amyloid Precursor Protein Cleavage in Rat Ocular Hypertension Invest. Ophthalmol. Vis. Sci., April 1, 2002; 43(4): 1077 - 1087. [Abstract] [Full Text] [PDF]

				F. M. S. DE VRIJ, J. A. SLUIJS, L. GREGORI, D. F. FISCHER, W. T. J. M. C. HERMENS, D. GOLDGABER, J. VERHAAGEN, F. W. VAN LEEUWEN, and E. M. HOL Mutant ubiquitin expressed in Alzheimer's disease causes neuronal death1 FASEB J, December 1, 2001; 15(14): 2680 - 2688. [Abstract] [Full Text] [PDF]

				G. Perry, X. Zhu, and M. A. Smith Do Neurons Have a Choice in Death? Am. J. Pathol., January 1, 2001; 158(1): 1 - 2. [Full Text] [PDF]