In this request to extend the MERIT application for an additional five years, we have focused on the major developments in both progress and plans for the future research. The last four years has seen very exciting developments in our conception of the pathogenesis of Alzheimer's disease, and the development of a novel, testable hypothesis. This hypothesis links the development of tau pathology, the activationof components of the cell cycle and neuronal degeneration, which may be due to the activation of the abl family of protein tyrosine kinases. With the support of this MERIT extension we plan direct testing of this hypothesis. If the hypothesis is supported by the work proposed, there will be direct and simple paths to new therapeutics for Alzheimer's disease. Although this project could be considered "high risk" research, the rewards will be considerable if it is successful. In the application, the progress leading to the development of the new hypothesis is reviewed, and the research plan is designed to rigorously assess it's validity through the characterization of new transgenic mice. Parallel studies in human brain and cell culture, supported by other finds, will provide additional relevant information.
The specific aims of this application are: 1. To establish whether c-abl or Arg activation occurs in the hTau mouse prior to cell cycle activation and neuronal death. 2. To construct and analyze transgenic mice with inducible, neuron-specific expressionof constitutively active c-abl. Similar mice with inducible, neuron-specific expression of constitutively active Arg will also be made. The prediction is that expression of the constitutively active abl kinases will result in cell cycle activation, tau (and perhaps amyloid) pathology, and cell death. 3. Assuming that neuron-specific expression of constitutively active c-abl (and/or Arg) does cause neuronal pathology, mice with inducible, neuron-specific expression of kinase-defective c-abl or Arg will also be made. 4. To examine the role of tau in cell cycle mediated cell death. The c-abl and Arg mice made under specific aim 2 will be crossed into the tau knockout, and into mice with the human tau gene, to examine the influence of tau on the expressionof pathology.
|Forest, Stefanie K; Acker, Christopher M; d'Abramo, Cristina et al. (2013) Methods for measuring tau pathology in transgenic mouse models. J Alzheimers Dis 33:463-71|
|Acker, Christopher M; Forest, Stefanie K; Zinkowski, Ray et al. (2013) Sensitive quantitative assays for tau and phospho-tau in transgenic mouse models. Neurobiol Aging 34:338-50|
|d'Abramo, Cristina; Acker, Christopher M; Jimenez, Heidy T et al. (2013) Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity. PLoS One 8:e62402|
|Capiralla, Hemachander; Vingtdeux, Valerie; Zhao, Haitian et al. (2012) Resveratrol mitigates lipopolysaccharide- and A*-mediated microglial inflammation by inhibiting the TLR4/NF-*B/STAT signaling cascade. J Neurochem 120:461-72|
|Chapuis, Julien; Vingtdeux, Valérie; Capiralla, Hemachander et al. (2012) Gas1 interferes with A?PP trafficking by facilitating the accumulation of immature A?PP in endoplasmic reticulum-associated raft subdomains. J Alzheimers Dis 28:127-35|
|Koppel, Jeremy; Campagne, Fabien; Vingtdeux, Valérie et al. (2011) CALHM1 P86L polymorphism modulates CSF A? levels in cognitively healthy individuals at risk for Alzheimer's disease. Mol Med 17:974-9|
|Chapuis, Julien; Vingtdeux, Valerie; Campagne, Fabien et al. (2011) Growth arrest-specific 1 binds to and controls the maturation and processing of the amyloid-beta precursor protein. Hum Mol Genet 20:2026-36|
|Vingtdeux, Valerie; Chandakkar, Pallavi; Zhao, Haitian et al. (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-* peptide degradation. FASEB J 25:219-31|
|Conejero-Goldberg, C; Hyde, T M; Chen, S et al. (2011) Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype. Mol Psychiatry 16:836-47|
|Vingtdeux, Valerie; Davies, Peter; Dickson, Dennis W et al. (2011) AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies. Acta Neuropathol 121:337-49|
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