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Magnetic Nanoparticle Hyperthermia-Mediated Clearance of Beta-amyloid Plaques: Implications in the Treatment of Alzheimer’s Disease

Dyne, Eric D
http://rave.ohiolink.edu/etdc/view?acc_num=kent1618706341759415

Abstract Details

2021, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by the accumulation of beta-amyloid plaques and neurofibrillary hyperphosphorylated tau tangles. According to the most recent report from the U.S. Centers for Disease Control and Prevention, Alzheimer’s disease is the 6th leading cause of death in the United States and the number of cases as increased almost 150% in the last 20 years in the United States. The disease starts as a subtle change in memory that progresses into noticeable cognitive decline, often referred to as mild cognitive impairment, and progresses into severe and pervasive memory loss. One of the hallmarks of Alzheimer’s disease is the accumulation of the misfolded protein product of the amyloid precursor protein, beta-amyloid. Beta-amyloid has been long considered and widely supported by genetics and biochemical observation to promote Alzheimer’s disease pathology. One of the earliest and long-supported theories, the amyloid hypothesis, posits beta-amyloid accumulation as having a central role in the pathogenesis of Alzheimer’s disease as a promoter of tau seeding and inflammatory signaling which causes immune dysfunction. Beta-amyloid therapeutics represent the majority of the clinical trial candidates for Alzheimer’s disease therapeutics. Recent clinical failures of anti-beta-amyloid trials, including Aducanumab and Gantenerumab, have raised concerns for the ability to manage beta-amyloid accumulation. The current pipeline of drugs targeting both beta-amyloid and tau are ineffective; therefore warranting alternative therapeutic options. A possible alternative non-pharmacological option for targeting beta-amyloid plaque aggregation is using energy to disrupt large beta-amyloid plaques into smaller fragments that may be cleared by microglia, the innate immune cells of the brain. One manner in which we can generate sufficient energy in a minimal to non-invasive safe manner is to use an alternating magnetic field (AMF). When conductive materials, such as superparamagnetic materials, are exposed to AMF, a controllable amount of thermal energy can be generated. The use of high-frequency alternating magnetic field generation has been used for many biomedical applications such as tumor resection and biofilm targetting. It has been observed that beta-amyloid plaques are held together by both hydrogen bonds and hydrophobic interactions within the beta-amyloid plaque structure. Our approach relies upon the interaction between 20nm superparamagnetic iron (II,III) oxide (Fe3O4) nanoparticles (MNP) and remote application of mild hyperthermia by an external magnetic field. After successful fragmentation, microglia processed the fragmented beta-amyloid for removal. It is hypothesized that the removal of the beta-amyloid plaques will attenuate pro-inflammatory signaling and our results demonstrated attenuation of several pro-inflammatory genes after exposure to mild hyperthermia. The application of mild hyperthermia to microglia induces professional chaperones known as heat shock proteins (HSP)7. These proteins play a vital role in the proper configuration of proteins but also act as antigen presenting cells. It is hypothesized that approximately 30% of newly synthesized proteins are not properly folded or formed Heat shock protein functionally should remove beta-amyloid, however, this does not seem to happen in Alzheimer’s disease. The use of mild-hyperthermia promotes a heat-stress response that activates HSP expression. We hypothesize that HSP70, a member of the HSP family involved with phagocytosis and autophagy, may produce a functional role of microglia towards clearing the beta-amyloid fragments. This study will address the specific aims using isolated human microglia from an adult patient (C20) microglia as our in vitro model organism. Beyond the depths of this dissertation, additional work will characterize our approach in an in vivo model of AD to further validate our in vitro observations. The use of human microglia provides our approach the opportunity of continuity with human reagents and understanding the human transcriptomic response to treatment. Further, the cell line chosen is superior to other commercially available cell lines in that the C20 cells readily endocytosed beta-amyloid fragments, released a wide variety of signaling molecules, and were IBA1 positive; all features were seen to be altered in the commercially available HMC3 cell line. Collectively, we propose using mild-hyperthermia to disrupt large beta-amyloid plaques via magnetic nanoparticles to reduce inflammatory signaling and promote clearance, possibly mediated by heat-shock induced HSP70.
Min-Ho Kim, Ph.D. (Advisor)
Fayez Safadi, Ph.D. (Advisor)
Colleen Novak, Ph.D. (Committee Chair)
Gary Koski, Ph.D. (Committee Member)
Songping Huang, Ph.D. (Committee Member)
216 p.
Biomedical Engineering; Biomedical Research; Nanoscience; Nanotechnology; Neurobiology; Neurology; Neurosciences
Nanoparticles; microglia; Alzheimers disease; beta amyloid; electron microscopy; glia; neurodegeneration; biomedical engineering; immunology; alternating magnetic field; heat shock protein; autophagy; endocytosis; morphology; neuroinflammation

Recommended Citations

Citations

  • Dyne, E. D. (2021). Magnetic Nanoparticle Hyperthermia-Mediated Clearance of Beta-amyloid Plaques: Implications in the Treatment of Alzheimer’s Disease [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1618706341759415

    APA Style (7th edition)

  • Dyne, Eric. Magnetic Nanoparticle Hyperthermia-Mediated Clearance of Beta-amyloid Plaques: Implications in the Treatment of Alzheimer’s Disease. 2021. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1618706341759415.

    MLA Style (8th edition)

  • Dyne, Eric. "Magnetic Nanoparticle Hyperthermia-Mediated Clearance of Beta-amyloid Plaques: Implications in the Treatment of Alzheimer’s Disease." Doctoral dissertation, Kent State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=kent1618706341759415

    Chicago Manual of Style (17th edition)

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© 2021, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.