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dc.contributor.advisorYan, Shirley S
dc.contributor.authorNolte, Erika D
dc.date.accessioned2019-09-06T19:34:57Z
dc.date.available2019-09-06T19:34:57Z
dc.date.issued2019-05-31
dc.date.submitted2019
dc.identifier.otherhttp://dissertations.umi.com/ku:16510
dc.identifier.urihttp://hdl.handle.net/1808/29549
dc.description.abstractAlzheimer’s disease (AD) is the sixth leading cause of death in United States, affecting more than five million people every year. Despite substantial research into the topic, including over a hundred thousand research papers on the topic and nearly a billion dollars per year in funding, no drugs have been approved by the FDA to prevent, slow, or cure AD. Upon discovering that patients with Alzheimer’s disease had increased Cyclophilin D (CypD), a key mitochondrial matrix protein responsible for the initiation of mitochondrial apoptosis, we generated models of tau-induced AD with altered CypD expression. CypD overexpression (OE) mice were successfully used to model more severe AD pathology. These mice showed increased levels of hyperphosphorylated tau (HPT). Additionally, these mice showed mitochondrial failure in an age dependent manner. Synaptic and neuronal loss were also identified in an age dependent manner. Finally, cognitive impairments were detected using an open field study and a daily task performance study. CypD knock out (KO) mice were used to model the potential therapeutic effects of lowering CypD in an AD model. These mice showed an amelioration of every AD biomarker tested. CypD KO mice showed lower HPT loads and normalized mitochondrial function. There was no detectable loss of synaptic terminals in the CypD KO line, and there was no loss of cognitive function in either open field or a daily task performance test. A small molecule CypD inhibitor created in our lab was used in a tau-induced model of AD to attempt to create the significant improvements seen with genetic ablation of CypD. This compound was determined to be safe for use in mice after testing in cell cultures revealed that it was non-toxic and effective at preventing Aβ-induced cellular death. In mice, the CypD inhibitor reduced HPT accumulation, restored mitochondrial function, and prevented cognitive declines without inducing any apparent toxicity in the mice.
dc.format.extent143 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectPharmacology
dc.subjectAging
dc.subjectAlzheimer's disease
dc.subjectMitochondria
dc.subjectTau
dc.titleCyclophilin D as a potential therapeutic target for Alzheimer’s disease
dc.typeDissertation
dc.contributor.cmtememberDobrowsky, Rick
dc.contributor.cmtememberShi, Holgian
dc.contributor.cmtememberSmith, Adam
dc.contributor.cmtememberMuma, Nancy
dc.contributor.cmtememberGamblin, Chris
dc.thesis.degreeDisciplinePharmacology & Toxicology
dc.thesis.degreeLevelPh.D.
dc.identifier.orcidhttps://orcid.org/0000-0002-3690-3581
dc.rights.accessrightsopenAccess


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