The two major hallmarks of Alzheimers disease (AD) are amyloid plaques and neurofibrillary tangles (NFTs). Evidence suggests that the main component of amyloid plaques, â-amyloid peptide (Aâ) facilitates tau pathology via activation of specific kinases. Both glycogen synthase kinase-3â (GSK-3â) and cyclin-dependent kinase 5 (cdk5) have been demonstrated to be activated by Aâ and contribute to tau hyperphosphorylation.
Recently, c-Abl has been implicated in Aâ-facilitated tau pathology by in vitro model systems. Alvarez et al. reported that c-Abl could be activated by Aâ in primary cultured neurons (Alvarez et al. 2004), and Derkinderen et al. found a novel phosphorylation site in paired helical filament tau (Tyr 394) that could be phosphorylated by c-Abl (Derkinderen et al. 2005). Moreover, Aâ has been shown to bind integrin receptors on the cell surface and transduce a signal from the extracellular space to the cell interior, regulating the cytoskeleton and/or gene transcription (Caltagarone, Jing et al. 2007). c-Abl can also be activated by integrin activation. Therefore, we hypothesize that c-Abl is associated with Aâ-facilitated tau phosphorylation via integrin binding and activation, contributing to the generation of AD pathology. We tested this hypothesis by examining the expression and distribution of c-Abl in the human hippocampus and by characterizing c-Abl interacting proteins in AD brain.
We discovered that the activation state of c-Abl was altered during AD progression and c-Abl was associated with phospho-tau during AD. Preliminary co-immunoprecipitation data
also suggested a possible association of c-Abl with another integrin signaling protein, paxillin. This study is the first to examine the expression and localization of c-Abl in healthy control and AD hippocampus, which contributes to our understanding of the functional role for c-Abl in AD pathogenesis. Interestingly, c-Abl was localized to granulovacuolar degeneration bodies (GVDs) during late-stage AD, a novel discovery that identifies a new protein component of GVDs in AD.
Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08292008-125131 |
Date | 02 September 2008 |
Creators | Jing, Zheng |
Contributors | Teresa G. Hastings, Robert Bowser, Ruth Perez, J. Patrick Card, Don DeFranco |
Publisher | University of Pittsburgh |
Source Sets | University of Pittsburgh |
Language | English |
Detected Language | English |
Type | text |
Format | application/pdf |
Source | http://etd.library.pitt.edu/ETD/available/etd-08292008-125131/ |
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