Caspase-cleavage of Tau in Alzheimer's disease
Introduction: Recent studies have suggested that proteolytic cleavage of tau by caspases may be an important event linking beta-amyloid with neurofibrillary tangles in Alzheimer's disease (AD). These studies suggest that caspase activation may play an important role in driving AD disease pathology and simply do not represent end-stage events associated with this disease. Hypothesis: Direct, functional evidence for the involvement of caspases in driving AD pathology is currently lacking. The current proposal will test directly the role of caspases in AD by blocking caspase activation in an AD transgenic mouse model and examining whether such inhibition prevents the pathology associated with these animals. Specific Aim 1: Crossing 3xTg-AD mice with Bcl-2 OE Tg mice will prevent the caspase cleavage of tau Specific Aim 2: Mice resulting from crossing 3xTg-AD mice with Bcl-2 OE Tg mice will exhibit fewer tangle alterations. Long-term goals: Direct evidence indicating a causative role for caspases in AD may stimulate the development of caspase inhibitors for their potential in treating this disease. In addition, results from this pilot study will provide the necessary feasibility and data for the development of a more comprehensive proposal examining all pathological aspects of these novel AD mice.
Kumasaka, D.K., Galvan, V., Head, E. and Rohn T.T. (2009). Caspase Cleavage of the Amyloid Precursor Protein is prevented After Overexpression of Bcl-2 in a Triple Transgenic Mouse Model of Alzheimer's Disease. Int J Physio Pathophysio Pharmacol 1(1):48-56
Rohn, T.T. (2009). Cytoplasmic Inclusions of TDP-43 in Neurodegenerative Diseases: A Potential Role for Caspases. Histology and Histopathology (Invited Review, 24(8):1081-1086).
Rohn, T.T. and Kokoulina, P. (2009). Caspase-cleaved TAR DNA-binding protein-43 in Pick's disease. Int, J. Physio. Pathophysio. Pharmacol. 1(1):25-32
Rohn, T.T., Kokoulina, P., Eaton, C.R. and Poon, W.W. (2009). Caspase Activation in Transgenic Mice with Alzheimer-like Pathology: Results From a Pilot Study Utilizing The Caspase Inhibitor, Q-VD-OPh. Int J Clin Exp Med. 2009; 2(4): 300-308. Published online 2009 November 5
Rohn, T.T. (2010). The Role of Caspases in Alzheimer's Disease; Potential Novel Therapeutic Opportunities. Invited Review, Apoptosis Journal, (Feb 3. [Epub ahead of print])
Kokoulina, P. and Rohn, T.T. (2010). Caspase-cleaved TAR DNA-binding protein-43 in Parkinson's disease and dementia with Lewy bodies. Neurodegenerative Diseases, (In Press).[PMID:nd][link not available]
First published on: June 10, 2008
Last modified on: September 2, 2010