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A棺-mediated Bioenergetic and Metabloic Abnormalities: Implications of the Antioxidant Pathway Modulation for Alzheimer's Disease Therapy
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | A棺-mediated Bioenergetic and Metabloic Abnormalities: Implications of the Antioxidant Pathway Modulation for Alzheimer's Disease Therapy. |
| 개인저자 | Sotolongo, Krystal M. |
| 단체저자명 | New York University. Basic Medical Science. |
| 발행사항 | [S.l.]: New York University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 207 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-05B. Dissertation Abstract International |
| ISBN | 9781392512265 |
| 학위논문주기 | Thesis (Ph.D.)--New York University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-05, Section: B.
Advisor: Rostagno, Agueda |
| 이용제한사항 | This item must not be sold to any third party vendors.This item must not be added to any third party search indexes. |
| 요약 | Alzheimer's disease (AD) is a complex neurodegenerative disorder neuropathologically characterized by the presence of parenchymal amyloid deposits, intraneuronal neurofibrillary tangles and synaptic loss. In AD patients, glucose hypometabolism, downregulation of central elements for oxidative phosphorylation, reduced ATP production, and enhanced reactive oxygen species (ROS) generation coexist-sometimes preceding-synaptic alterations and clinical manifestations of the disease. Mitochondria play essential roles in maintaining the high levels of brain energy demands and, as a major consumers of oxygen, they are also the most important generators of ROS. Thus, it is not surprising that mitochondrial dysfunction /oxidative stress are tightly linked to synaptic loss and AD pathophysiology. To date, the mechanistic links among ROS homeostasis, cellular metabolic alterations, and changes in cell bioenergetics, particularly at the level of synapsis and in relation to oligomeric forms of amyloid-棺 (oligA棺), still remain elusive. We hypothesize that oligA棺 induces neuronal mitochondrial dysfunction by altering oxidative phosphorylation and cellular redox state homeostasis and propose that these events are susceptible to pharmacological interventions through the use of small molecules capable of restoring mitochondrial bioenergetics parameters.Studies in transgenic AD mouse models showed decreased synaptic and mitochondrial protein levels, ATP production, overall mitochondrial function, and increased oxidative stress, mimicking what has been reported in AD patients. Our findings using neuronal cell culture paradigms demonstrate that oligA棺 induces detrimental changes in mitochondrial function with loss of mitochondrial membrane potential, release of cytochrome C, enhanced ROS generation and induction of apoptosis. Assessment of global energy metabolism in real time after sequential addition of different inhibitors of the mitochondrial metabolic pathways, demonstrate an oligA棺-mediated reduction in oxygen consumption affecting basal and maximal respiration capacity and causing a decrease in ATP production. Pharmacologic targeting of oligA棺-challenged neurons with small molecules of known antioxidant activity restored mitochondrial integrity/function, rescuing metabolic and bioenergetics changes induced by oligA棺. Search for the mechanistic link identified the transcription factor Nrf2 as the main target of these compounds, inducing Nrf2 activation, nuclear translocation and effectively triggering the Nrf2 downstream antioxidant response, increasing SOD-1 ad HO-1 production mediated through the PI3K/GSK-3 axis. Overall, our study provides insights into the complex molecular mechanisms triggered by oligA棺 which profoundly affect mitochondrial performance and highlights the potential of antioxidant pharmacologic targeting to ameliorate metabolic/bioenergetics alterations. |
| 일반주제명 | Neurosciences. Pathology. |
| 언어 | 영어 |
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