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The localization of c-Abl in Alzheimer's disease.

Jing, Zheng (2008) The localization of c-Abl in Alzheimer's disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The two major hallmarks of Alzheimer's 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 dataalso 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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Jing, Zhengzhj1@pitt.eduZHJ1
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBowser,
Committee ChairHastings, Teresa
Committee MemberDeFranco, Dondod1@pitt.eduDOD1
Committee MemberCard, J. Patrickcard@pitt.eduCARD
Committee MemberPerez, Ruthperezrg@pitt.eduPEREZRG
Date: 2 September 2008
Date Type: Completion
Defense Date: 14 July 2008
Approval Date: 2 September 2008
Submission Date: 29 August 2008
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Alzheimer's disease; c-Abl; human hippocampus
Other ID:, etd-08292008-125131
Date Deposited: 10 Nov 2011 20:01
Last Modified: 15 Nov 2016 13:49


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