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Receptors for Amyloid Beta and Pharmacologic Intervention in Alzheimer's Disease
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Receptors for Amyloid Beta and Pharmacologic Intervention in Alzheimer's Disease. |
| 개인저자 | Smith, Levi M. |
| 단체저자명 | Yale University. Cell Biology. |
| 발행사항 | [S.l.]: Yale University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 148 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-04B. Dissertation Abstract International |
| ISBN | 9781088320273 |
| 학위논문주기 | Thesis (Ph.D.)--Yale University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Advisor: Strittmatter, Stephen M. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Alzheimer's disease is the leading cause of dementia worldwide and is an impending global health crisis. By 2030, it is projected that nearly 75 million people will be living with dementia worldwide at an annual societal economic cost of 2 trillion U.S. dollars. Despite Alzheimer's disease being first described more than a century ago, there are still no treatments capable of curing, preventing, or even slowing disease progression. Recent advances in our understanding of the molecular mechanisms of neurotoxicity in Alzheimer's disease have produced some of the greatest strides towards disease modifying therapeutics that the field has seen. Our understanding of how the pathognomonic amyloid beta in the extracellular space of the brain causes neurotoxicity has been a burgeoning area of research. Intense focus in this area of research has produced lines of research which have described multiple pathways towards neurotoxicity but have not prioritized cross-validation and reconciliation of disparate findings. Here, I describe my experimental efforts to determine the relative contributions and disease relevance of over a dozen receptors for amyloid beta reported across twenty years of research. With this new understanding of which proteins play a role in this principal event in the transduction of neurotoxicity, I go on to discover and describe chemical compounds capable of completely preventing neurotoxic amyloid beta oligomers from binding to neurons. Using cell culture and animal models of disease, I discover that these compounds prevent neurotoxicity, restore synapse deficits, and rescue memory impairment in a mouse model of Alzheimer's disease. I go on to describe the implementation of the treatment-withdrawal study design in a preclinical model of Alzheimer's disease and distinguish the disease modifying effects of the Fyn kinase inhibitor saracatinib (AZD0530) from the symptomatic effects of memantine, a medication FDA approved for the treatment of Alzheimer's disease. The superiority of saracatinib in these experiments provides not only encouragement for its clinical development, but provides the field of Alzheimer's disease drug development with a new benchmark for preclinical drug development which could help to improve the quality of investigational drugs that enter clinical development. |
| 일반주제명 | Neurosciences. Cellular biology. Pharmacology. |
| 언어 | 영어 |
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