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PREVENTING STRESS SIGNALING AND INCREASED NEUROINFLAMMATION ALLEVIATES ALZHEIMER’S-LIKE PATHOLOGY IN MICE OVEREXPRESSING THE APP INTRACELLULAR DOMAIN (AICD)

Margevicius, Daniel Robert
http://orcid.org/0000-0002-2279-1590
http://rave.ohiolink.edu/etdc/view?acc_num=case1433275461

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Alzheimer’s disease (AD) is a devastating neurodegenerative disease that represents an immense challenge to public health and wellness. AD is defined by extracellular accumulations of amyloid beta (Aß), a protein heavily associated with AD pathogenesis, into senile plaques, and intracellular accumulations of tau into neurofibrillary tangles. The primary focus in the field has been on how Aß accumulation exhibits toxicity and contributes to AD. However, increasing evidence suggests Aß is not the only effector mediating AD pathogenesis. Aß is released from proteolytic processing of a larger protein known as Amyloid Precursor Protein (APP), which is heavily implicated in AD. The proteolytic process that releases Aß from APP also releases increased functional levels of the APP intracellular domain (AICD). AICD is cytotoxic in vitro, and in vivo can mediate many AD-like pathologies in transgenic mice overexpressing AICD (AICD-Tg mice). The cell signaling mechanisms mediating this pathogenesis are unknown. AICD binds many other cell signaling proteins. One of these proteins is c-Jun N-terminal Kinase (JNK)-Interacting Protein-1 (JIP1). JIP1 mediates stress-specific JNK activation. This work demonstrates increased presence of AICD can contribute to AD pathogenesis in vivo through JIP1. Increased JNK activation can also result in increased inflammatory activation. Inflammation is also heavily implicated in AD pathogenesis. Therefore, AICD’s effects on JIP1-mediated JNK activation may contribute to AD pathogenesis by serving to activate increasing inflammation. Anti-inflammatory treatments administered peripherally to AICD-Tg mice alleviate pathogenesis. Intravenous immunoglobulin (IVIg) is a robustly anti-inflammatory reagent being investigated as a clinical treatment for AD. To confirm if neuroinflammation can mediate pathogenesis in AICD-Tg mice IVIg was administered both prophylactically (before pathology development) and therapeutically (after pathology had already developed) in AICD-Tg mice. Mice treated prophylactically do not develop pathology, while mice treated therapeutically still demonstrate pathology and AD-related deficits. This suggests prophylactic treatment of AICD-mediated AD pathogenesis is more efficacious in alleviating AD pathogenesis, and suggests neuroinflammation, possibly mediated through the AICD-JIP1 interaction, drives AICD-mediated pathogenesis.
Sanjay Pimplikar, PhD (Advisor)
Brian McDermott, PhD (Committee Chair)
Michael Parsons, PhD (Committee Member)
Bruce Lamb, PhD (Committee Member)
Hoonkyo Suh, PhD (Committee Member)
235 p.
Biology; Cellular Biology; Health Sciences; Medicine; Neurobiology; Neurosciences
Alzheimer; Amyloid Precursor Protein; AICD; tau; JNK; JNK interacting protein 1; intravenous immunoglobulin; neuroinflammation; therapeutic; cell biology;

Recommended Citations

Citations

  • Margevicius, D. R. (2015). PREVENTING STRESS SIGNALING AND INCREASED NEUROINFLAMMATION ALLEVIATES ALZHEIMER’S-LIKE PATHOLOGY IN MICE OVEREXPRESSING THE APP INTRACELLULAR DOMAIN (AICD) [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1433275461

    APA Style (7th edition)

  • Margevicius, Daniel. PREVENTING STRESS SIGNALING AND INCREASED NEUROINFLAMMATION ALLEVIATES ALZHEIMER’S-LIKE PATHOLOGY IN MICE OVEREXPRESSING THE APP INTRACELLULAR DOMAIN (AICD). 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1433275461.

    MLA Style (8th edition)

  • Margevicius, Daniel. "PREVENTING STRESS SIGNALING AND INCREASED NEUROINFLAMMATION ALLEVIATES ALZHEIMER’S-LIKE PATHOLOGY IN MICE OVEREXPRESSING THE APP INTRACELLULAR DOMAIN (AICD)." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1433275461

    Chicago Manual of Style (17th edition)

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© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.